|
Compound was evaluated for its binding affinity towards beta-1 adrenergic receptor in rat heart membrane by displacing [125I]- iodocyanopindolol
|
None
|
600.0
nM
|
|
Journal : J. Med. Chem.
Title : Disodium (R,R)-5-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]-amino] propyl]-1,3-benzodioxole-2,2-dicarboxylate (CL 316,243). A potent beta-adrenergic agonist virtually specific for beta 3 receptors. A promising antidiabetic and antiobesity agent.
Year : 1992
Volume : 35
Issue : 16
First Page : 3081
Last Page : 3084
Authors : Bloom JD, Dutia MD, Johnson BD, Wissner A, Burns MG, Largis EE, Dolan JA, Claus TH.
|
Compound was evaluated for beta adrenergic binding affinity towards Beta-1 adrenergic receptor of rat brain
|
None
|
80.0
nM
|
|
Journal : J. Med. Chem.
Title : Conformational effects on the activity of drugs. 13. A revision of previously proposed models for the activation of alpha- and beta-adrenergic receptors.
Year : 1992
Volume : 35
Issue : 6
First Page : 1009
Last Page : 1018
Authors : Macchia B, Balsamo A, Breschi MC, Lapucci A, Lucacchini A, Macchia F, Manera C, Martinelli A, Martini C, Martinotti E.
Abstract : The alpha 1-, alpha 2-, beta 1-, and beta 2-adrenergic properties of the 2-(3,4-dihydroxyphenyl)morpholines 3 and 4 (2-DPMs), of the 3-(3,4-dihydroxyphenyl)-3-piperidinols 5 and 6 (3-DPPs), and of the trans-2-amino-5,6-dihydroxytetrahydronaphthalen-1-ols 7 and 8 and the trans-2-amino-6,7-dihydroxytetrahydronaphthalen-1-ols 9 and 10 (2-ADTNs) were evaluated in vitro both by radioligand binding assays and by functional tests on isolated preparations and compared with those of norepinephrine (NE, 1) and isoprenaline (ISO, 2). Through a comparison of the stereostructures of the compounds examined with their biopharmacological properties, it was possible to revise previously proposed molecular models for the direct activation of alpha- and beta-adrenergic receptors. The revised models (A-C) provided information about the conformational requirements of adrenergic drugs, which substantially fit in with the results of several published studies involving conformationally-restricted adrenoceptor agonists. The different position of the catecholic hydroxyl groups in model B, which refers to the alpha 2 receptors, and in model C, which refers to the beta receptors, confirms the importance of the rotameric position of the aromatic ring of catecholamines in the interaction with the alpha- and beta-adrenergic receptor.
|
Compound was evaluated for the inhibition of binding of [3H]dihydroalprenolol from beta-1 adrenergic receptor of rat cerebral cortical membranes
|
None
|
670.0
nM
|
|
Journal : J. Med. Chem.
Title : Effect of fluorine substitution on the adrenergic properties of 3-(tert-butylamino)-1-(3,4-dihydroxyphenoxy)-2-propanol.
Year : 1991
Volume : 34
Issue : 3
First Page : 1063
Last Page : 1068
Authors : Adejare A, Nie JY, Hebel D, Brackett LE, Choi O, Gusovsky F, Padgett WL, Daly JW, Creveling CR, Kirk KL.
Abstract : The 2- and 6-fluoro derivatives of the potent beta-adrenergic agonist 3-(tert-butylamino)-1-(3,4-dihydroxyphenoxy)-2-propanol were prepared and their adrenergic properties examined. The order of potency was as follows: beta-adrenergic activity (simulation of cyclic AMP formation in C6 glioma cells), 2-F = parent much greater than 6-F; beta 1-activity (rate of contraction, guinea pig atria), parent greater than 2-F much greater than 6-F; beta 2-activity (relaxation of guinea pig tracheal strip), 2-F greater than parent much greater than 6-F. The affinity of the 2-fluoro analogue for beta 1-adrenergic receptors (inhibition of the specific binding of [3H]dihydroalprenolol, rat cerebral cortical membranes) was 2 times greater, while the 6-fluoro analogue was 1450 times less than the parent. These results suggest that the aromatic rings of phenoxypropanolamine adrenergic agonists and phenylethanolamine adrenergic agonists bind in similar fashion to the adrenergic receptor, and that if interactions between fluorine and the side-chain hydroxyl group are critical in defining beta-adrenergic selectivity, the interactions are similar in both phenoxypropanolamines and phenylethanolamines.
|
Tested for binding affinity against beta-1 adrenergic receptor in rat brain using [3H]-CGP- 26505 as radioligand
|
None
|
80.0
nM
|
|
Journal : J. Med. Chem.
Title : Conformationally restrained analogs of sympathomimetic catecholamines. Synthesis, conformational analysis, and adrenergic activity of isochroman derivatives.
Year : 1993
Volume : 36
Issue : 21
First Page : 3077
Last Page : 3086
Authors : Macchia B, Balsamo A, Breschi MC, Chiellini G, Lapucci A, Macchia M, Manera C, Martinelli A, Martini C, Scatizzi R.
Abstract : In previous papers dealing with the study of the conformations and the biopharmacological activity of conformationally restrained analogs of sympathomimetic catecholamines (NE and ISO), proposals were advanced for the three-dimensional molecular models A, B, and C; these models provided information about the steric requirements for the direct activation of alpha 1, alpha 2,beta 1, and beta 2 adrenoceptors, respectively. The 1-(aminomethyl)-6,7-dihydroxyisochromans 11 and 12 and the 1-(aminomethyl)-5,6-dihydroxyisochromans 13 and 14 (1-AMDICs) are two different types of semirigid analogs of NE and ISO. The alpha 1, alpha 2, beta 1, and beta 2 adrenergic properties of the 1-AMDICs 11-14 were evaluated in vitro, both by radioligand binding assays and by functional tests on isolated preparations, and were compared with those of their parent compounds (NE and ISO). The results of a conformational study carried out by means of both 1H NMR spectrometry and theoretical calculations indicated that, in these 1-AMDICs, the presumed active groups (aryl moiety, amine nitrogen and benzylic ethereal oxygen) are in a spatial relationship corresponding to the one found for NE and ISO in their preferred conformations, which also proved to be the pharmacophoric conformation in the models A-C. By means of a comparison of the stereostructures of the 1-AMDICs 11-14 with their biopharmacological properties, it was possible to obtain a further definition of the model B with respect to the activation of the alpha 2 adrenoceptors; the superimposition of the 1-AMDICs 11 and 12 with the molecular model C made it possible to detect an area of the beta-adrenergic receptors which might hinder the fit of adrenergic drugs that are analogs of catecholamines with these receptors.
|
Compound was evaluated for beta adrenergic binding affinity towards beta-2 receptor of bovine lung
|
None
|
110.0
nM
|
|
Journal : J. Med. Chem.
Title : Conformational effects on the activity of drugs. 13. A revision of previously proposed models for the activation of alpha- and beta-adrenergic receptors.
Year : 1992
Volume : 35
Issue : 6
First Page : 1009
Last Page : 1018
Authors : Macchia B, Balsamo A, Breschi MC, Lapucci A, Lucacchini A, Macchia F, Manera C, Martinelli A, Martini C, Martinotti E.
Abstract : The alpha 1-, alpha 2-, beta 1-, and beta 2-adrenergic properties of the 2-(3,4-dihydroxyphenyl)morpholines 3 and 4 (2-DPMs), of the 3-(3,4-dihydroxyphenyl)-3-piperidinols 5 and 6 (3-DPPs), and of the trans-2-amino-5,6-dihydroxytetrahydronaphthalen-1-ols 7 and 8 and the trans-2-amino-6,7-dihydroxytetrahydronaphthalen-1-ols 9 and 10 (2-ADTNs) were evaluated in vitro both by radioligand binding assays and by functional tests on isolated preparations and compared with those of norepinephrine (NE, 1) and isoprenaline (ISO, 2). Through a comparison of the stereostructures of the compounds examined with their biopharmacological properties, it was possible to revise previously proposed molecular models for the direct activation of alpha- and beta-adrenergic receptors. The revised models (A-C) provided information about the conformational requirements of adrenergic drugs, which substantially fit in with the results of several published studies involving conformationally-restricted adrenoceptor agonists. The different position of the catecholic hydroxyl groups in model B, which refers to the alpha 2 receptors, and in model C, which refers to the beta receptors, confirms the importance of the rotameric position of the aromatic ring of catecholamines in the interaction with the alpha- and beta-adrenergic receptor.
|
Tested for binding affinity against beta-2 adrenergic receptor in bovine lung using [3H]DHA as radioligand
|
None
|
110.0
nM
|
|
Journal : J. Med. Chem.
Title : Conformationally restrained analogs of sympathomimetic catecholamines. Synthesis, conformational analysis, and adrenergic activity of isochroman derivatives.
Year : 1993
Volume : 36
Issue : 21
First Page : 3077
Last Page : 3086
Authors : Macchia B, Balsamo A, Breschi MC, Chiellini G, Lapucci A, Macchia M, Manera C, Martinelli A, Martini C, Scatizzi R.
Abstract : In previous papers dealing with the study of the conformations and the biopharmacological activity of conformationally restrained analogs of sympathomimetic catecholamines (NE and ISO), proposals were advanced for the three-dimensional molecular models A, B, and C; these models provided information about the steric requirements for the direct activation of alpha 1, alpha 2,beta 1, and beta 2 adrenoceptors, respectively. The 1-(aminomethyl)-6,7-dihydroxyisochromans 11 and 12 and the 1-(aminomethyl)-5,6-dihydroxyisochromans 13 and 14 (1-AMDICs) are two different types of semirigid analogs of NE and ISO. The alpha 1, alpha 2, beta 1, and beta 2 adrenergic properties of the 1-AMDICs 11-14 were evaluated in vitro, both by radioligand binding assays and by functional tests on isolated preparations, and were compared with those of their parent compounds (NE and ISO). The results of a conformational study carried out by means of both 1H NMR spectrometry and theoretical calculations indicated that, in these 1-AMDICs, the presumed active groups (aryl moiety, amine nitrogen and benzylic ethereal oxygen) are in a spatial relationship corresponding to the one found for NE and ISO in their preferred conformations, which also proved to be the pharmacophoric conformation in the models A-C. By means of a comparison of the stereostructures of the 1-AMDICs 11-14 with their biopharmacological properties, it was possible to obtain a further definition of the model B with respect to the activation of the alpha 2 adrenoceptors; the superimposition of the 1-AMDICs 11 and 12 with the molecular model C made it possible to detect an area of the beta-adrenergic receptors which might hinder the fit of adrenergic drugs that are analogs of catecholamines with these receptors.
|
Affinity for cow beta-2 adrenergic receptor by measuring displacement (-)-[3H]dihydroalprenolol (DHA)
|
None
|
330.0
nM
|
|
Journal : J. Med. Chem.
Title : Quantitative evaluation of the beta 2-adrenoceptor affinity of phenoxypropanolamines and phenylethanolamines.
Year : 1985
Volume : 28
Issue : 9
First Page : 1328
Last Page : 1334
Authors : IJzerman AP, Aué GH, Bultsma T, Linschoten MR, Timmerman H.
Abstract : The influence of the aromatic moiety of beta-adrenoceptor ligands on the affinity for the beta 2-adrenoceptor has been studied. Three classes of ligands have been examined, viz. N-isopropyl- and N-tert-butylphenylethanolamines and N-isopropylphenoxypropanolamines. Computer-assisted analysis of the inhibition by any of these ligands of the specific (-)-[3H]dihydroalprenolol binding to the beta 2-adrenoceptors of a bovine skeletal muscle preparation in the presence of GppNHp (10(-4) M) yielded the affinities of these ligands at pH 7.5. The obtained values were adjusted for the amounts of cations present at this pH value. A significant correlation was found between the calculated lipophilicities and the experimentally determined affinities in the three classes. Furthermore, steric factors seem to play an important role, as these correlations were improved by the introduction of steric parameters for the aromatic substituents in the regression analyses. From the established equations it is concluded that the phenoxypropanolamine derivatives bind to the beta 2-adrenoceptor in a way different from that of the ligands in both ethanolamine classes.
|
Evaluated for Beta adrenergic receptor agonistic property in isolated guinea pig atria
|
Cavia porcellus
|
30.0
nM
|
|
Journal : J. Med. Chem.
Title : Syntheses and adrenergic agonist properties of ring-fluorinated isoproterenols.
Year : 1982
Volume : 25
Issue : 6
First Page : 680
Last Page : 684
Authors : Kirk KL, Cantacuzène D, Collins B, Chen GT, Nimit Y, Creveling CR.
Abstract : 2-Fluoro-, 5-fluoro-, and 6-fluoroisoproterenol were synthesized by reduction of the Schiff base formed between the corresponding ring-fluorinated 3,4-bis(benzyloxy)phenethanolamine and acetone, followed by reductive debenzylation in the presence of oxalic acid to yield crystalline neutral oxalates. The apparent beta-adrenergic potencies were determined in the isolated guinea pig atria. 2-Fluoro- and 5-fluoroisoproterenol were equipotent with (+/-)-isoproterenol, while 6-fluoroisoprotenol was virtually inactive. No alpha-adrenergic agonist activity (guinea pig aorta) was shown by any of the fluoroisoproterenols. Displacement of alpha- and beta-specific radioligands from isolated membrane preparations from rat brain by the fluoroisoproterenols were in agreement with the responses of the organ preparations. Thus, the apparent fluorine-induced specificity is due to specificity at the receptor binding site. The effects of fluorine substitution are discussed with regard to the apparent negative influence of the 6-fluoro substituent on the beta-agonist properties of isoproterenol, the lack of any increase in potency due to the 2-fluoro substituent, and the possibility of fluorine-induced changes in the electron density of the aromatic ring as a possible rational for the fluorine-induced specificity of both the fluoroisoproterenols and the fluoronoirepinephrines.
|
Binding Affinity against human beta-2 adrenergic receptor expressed in Chinese hamster ovary(CHO) cells was measured by using [125I]ICYP radioligand
|
None
|
676.08
nM
|
|
Journal : J. Med. Chem.
Title : 2-Amino-4-benzyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridines: novel selective beta3-adrenoceptor agonists.
Year : 1999
Volume : 42
Issue : 12
First Page : 2287
Last Page : 2294
Authors : Zheng W, Nikulin VI, Konkar AA, Vansal SS, Shams G, Feller DR, Miller DD.
Abstract : Trimetoquinol (TMQ, 7) is a potent nonselective beta-adrenoceptor (AR) agonist. Replacement of the catechol moiety of TMQ with a 2-aminothiazole group resulted in novel thiazolopyridine derivatives 9-11 which have been synthesized and evaluated for biological activity on human beta1-, beta2-, and beta3-AR. The Bischler-Napieralski reaction has been employed as a novel approach to construct the 2-amino-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine ring system. Although in radioligand binding studies analogues 9 and 10 did not show selectivity toward beta3-AR, they exhibited a high degree of selective beta3-AR agonist activity in functional assays. Moreover, the beta3-AR agonist activity of the 2-aminothiazole derivatives is abolished by N-acetylation (analogue 11) or ring opening (analogue 25). This illustrates the importance of the intact 2-amino-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine ring for beta3-AR activity.
|
Effective concentration against 125I]iodocyanopindolol(ICYP) binding to beta adrenergic receptor was determined
|
None
|
980.0
nM
|
|
Journal : J. Med. Chem.
Title : Conjugates of catecholamines. 5. Synthesis and beta-adrenergic activity of N-(aminoalkyl)norepinephrine derivatives.
Year : 1985
Volume : 28
Issue : 5
First Page : 634
Last Page : 642
Authors : Reitz AB, Sonveaux E, Rosenkranz RP, Verlander MS, Melmon KL, Hoffman BB, Akita Y, Castagnoli N, Goodman M.
Abstract : A novel series of N-aminoalkyl congeners and model derivatives of norepinephrine has been synthesized. Compounds that were structurally related to epinephrine were prepared from fully protected intermediates. Alternatively, isoproterenol-related compounds were synthesized via reductive amination of preformed methyl ketone derivatives with norepinephrine. The beta-adrenergic activities of these new compounds were assessed through measurement of intracellular cyclic AMP accumulation in S49 mouse lymphoma cells and displacement of iodocyanopindolol (ICYP) from membrane preparations. Congeners that contained an underivatized primary amine function exhibited virtually no activity in these assays. However, when this amine function was acylated (e.g., to an amide, carbamate, urea, sulfonamide, etc.), the products exhibited generally increased beta-adrenergic activity, which was, however, strongly dependent on the nature of the acylating group and also the length of the spacer. In particular, a benzyl carbamate derivative containing a branched, seven-carbon spacer group was 40 times more potent than isoproterenol in the in vitro S49 assay.
|
Inhibition of spontaneous contractions in isolated rat uterus
|
Rattus norvegicus
|
0.1
nM
|
|
Journal : J. Med. Chem.
Title : Relationship between stereochemistry and the beta3-adrenoceptor agonistic activity of 4'-hydroxynorephedrine derivative as an agent for treatment of frequent urination and urinary incontinence.
Year : 2003
Volume : 46
Issue : 1
First Page : 105
Last Page : 112
Authors : Tanaka N, Tamai T, Mukaiyama H, Hirabayashi A, Muranaka H, Ishikawa T, Kobayashi J, Akahane S, Akahane M.
Abstract : This report proposes a beta(3)-adrenoceptor (AR) selective agonist, 2-[2-chloro-4-(2-([(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino)ethyl)phenoxy]acetic acid (1a), as a novel agent for treating urinary bladder dysfunction. This compound and its relatives have a unique feature among beta(3)-AR agonists: two chiral carbons are adjacently structured on the left side of the molecule. To study the relationship between the stereoconfiguration of the vicinal chiral carbons in 1a and beta-AR agonistic activity, the four stereoisomers were synthesized via oxazolidinone prepared by intracyclization involving inversion of the beta-hydroxy group. The in vitro assays using rat atria for beta(1)-AR, rat uteri for beta(2)-AR, and ferret detrusor for beta(3)-AR showed that 1a possessed potent beta(3)-AR agonistic activity (EC(50) = 3.85 nM) and 3700- and 1700-fold selectivity for beta(3)-AR relative to beta(1)- and beta(2)-AR, respectively. Comparison of the four isomers revealed that the (alphaS,betaR)-compound (1a) was not only the most potent agonist but was also the most selective for beta(3)-AR. In the anesthetized rat, intravenous administration of 1a brought about a sufficient decrement of the intrabladder pressure (ED(50) = 12 microg/kg), and intraduodenal administration of 2a, which is the ethyl ester of 1a, led to same result (ED(50) = 0.65 mg/kg). Moreover, no effects on the cardiovascular system were observed in either test.
|
Agonistic activity for Beta-2 adrenergic receptor was assessed by it's inhibitory effect on spontaneous contractions in isolated rat uterus
|
None
|
0.1
nM
|
|
Journal : J. Med. Chem.
Title : Relationship between stereochemistry and the beta3-adrenoceptor agonistic activity of 4'-hydroxynorephedrine derivative as an agent for treatment of frequent urination and urinary incontinence.
Year : 2003
Volume : 46
Issue : 1
First Page : 105
Last Page : 112
Authors : Tanaka N, Tamai T, Mukaiyama H, Hirabayashi A, Muranaka H, Ishikawa T, Kobayashi J, Akahane S, Akahane M.
Abstract : This report proposes a beta(3)-adrenoceptor (AR) selective agonist, 2-[2-chloro-4-(2-([(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino)ethyl)phenoxy]acetic acid (1a), as a novel agent for treating urinary bladder dysfunction. This compound and its relatives have a unique feature among beta(3)-AR agonists: two chiral carbons are adjacently structured on the left side of the molecule. To study the relationship between the stereoconfiguration of the vicinal chiral carbons in 1a and beta-AR agonistic activity, the four stereoisomers were synthesized via oxazolidinone prepared by intracyclization involving inversion of the beta-hydroxy group. The in vitro assays using rat atria for beta(1)-AR, rat uteri for beta(2)-AR, and ferret detrusor for beta(3)-AR showed that 1a possessed potent beta(3)-AR agonistic activity (EC(50) = 3.85 nM) and 3700- and 1700-fold selectivity for beta(3)-AR relative to beta(1)- and beta(2)-AR, respectively. Comparison of the four isomers revealed that the (alphaS,betaR)-compound (1a) was not only the most potent agonist but was also the most selective for beta(3)-AR. In the anesthetized rat, intravenous administration of 1a brought about a sufficient decrement of the intrabladder pressure (ED(50) = 12 microg/kg), and intraduodenal administration of 2a, which is the ethyl ester of 1a, led to same result (ED(50) = 0.65 mg/kg). Moreover, no effects on the cardiovascular system were observed in either test.
|
Concentration required to effect a 50% relaxation of rat ferret detrusor basal tone
|
Mustela putorius furo
|
87.0
nM
|
|
Journal : J. Med. Chem.
Title : Relationship between stereochemistry and the beta3-adrenoceptor agonistic activity of 4'-hydroxynorephedrine derivative as an agent for treatment of frequent urination and urinary incontinence.
Year : 2003
Volume : 46
Issue : 1
First Page : 105
Last Page : 112
Authors : Tanaka N, Tamai T, Mukaiyama H, Hirabayashi A, Muranaka H, Ishikawa T, Kobayashi J, Akahane S, Akahane M.
Abstract : This report proposes a beta(3)-adrenoceptor (AR) selective agonist, 2-[2-chloro-4-(2-([(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino)ethyl)phenoxy]acetic acid (1a), as a novel agent for treating urinary bladder dysfunction. This compound and its relatives have a unique feature among beta(3)-AR agonists: two chiral carbons are adjacently structured on the left side of the molecule. To study the relationship between the stereoconfiguration of the vicinal chiral carbons in 1a and beta-AR agonistic activity, the four stereoisomers were synthesized via oxazolidinone prepared by intracyclization involving inversion of the beta-hydroxy group. The in vitro assays using rat atria for beta(1)-AR, rat uteri for beta(2)-AR, and ferret detrusor for beta(3)-AR showed that 1a possessed potent beta(3)-AR agonistic activity (EC(50) = 3.85 nM) and 3700- and 1700-fold selectivity for beta(3)-AR relative to beta(1)- and beta(2)-AR, respectively. Comparison of the four isomers revealed that the (alphaS,betaR)-compound (1a) was not only the most potent agonist but was also the most selective for beta(3)-AR. In the anesthetized rat, intravenous administration of 1a brought about a sufficient decrement of the intrabladder pressure (ED(50) = 12 microg/kg), and intraduodenal administration of 2a, which is the ethyl ester of 1a, led to same result (ED(50) = 0.65 mg/kg). Moreover, no effects on the cardiovascular system were observed in either test.
|
Beta adrenergic receptor agonistic activity for the stimulation of accumulation of cyclic AMP in cultured C6 glioma cells
|
None
|
7.0
nM
|
|
Journal : J. Med. Chem.
Title : Effect of fluorine substitution on the adrenergic properties of 3-(tert-butylamino)-1-(3,4-dihydroxyphenoxy)-2-propanol.
Year : 1991
Volume : 34
Issue : 3
First Page : 1063
Last Page : 1068
Authors : Adejare A, Nie JY, Hebel D, Brackett LE, Choi O, Gusovsky F, Padgett WL, Daly JW, Creveling CR, Kirk KL.
Abstract : The 2- and 6-fluoro derivatives of the potent beta-adrenergic agonist 3-(tert-butylamino)-1-(3,4-dihydroxyphenoxy)-2-propanol were prepared and their adrenergic properties examined. The order of potency was as follows: beta-adrenergic activity (simulation of cyclic AMP formation in C6 glioma cells), 2-F = parent much greater than 6-F; beta 1-activity (rate of contraction, guinea pig atria), parent greater than 2-F much greater than 6-F; beta 2-activity (relaxation of guinea pig tracheal strip), 2-F greater than parent much greater than 6-F. The affinity of the 2-fluoro analogue for beta 1-adrenergic receptors (inhibition of the specific binding of [3H]dihydroalprenolol, rat cerebral cortical membranes) was 2 times greater, while the 6-fluoro analogue was 1450 times less than the parent. These results suggest that the aromatic rings of phenoxypropanolamine adrenergic agonists and phenylethanolamine adrenergic agonists bind in similar fashion to the adrenergic receptor, and that if interactions between fluorine and the side-chain hydroxyl group are critical in defining beta-adrenergic selectivity, the interactions are similar in both phenoxypropanolamines and phenylethanolamines.
|
Inhibitory concentration required for displacement of Beta adrenergic receptor specific ligand [3H]dihydroalprenolol from rat brain cerebral cortical membranes
|
None
|
100.0
nM
|
|
Journal : J. Med. Chem.
Title : Syntheses and adrenergic agonist properties of ring-fluorinated isoproterenols.
Year : 1982
Volume : 25
Issue : 6
First Page : 680
Last Page : 684
Authors : Kirk KL, Cantacuzène D, Collins B, Chen GT, Nimit Y, Creveling CR.
Abstract : 2-Fluoro-, 5-fluoro-, and 6-fluoroisoproterenol were synthesized by reduction of the Schiff base formed between the corresponding ring-fluorinated 3,4-bis(benzyloxy)phenethanolamine and acetone, followed by reductive debenzylation in the presence of oxalic acid to yield crystalline neutral oxalates. The apparent beta-adrenergic potencies were determined in the isolated guinea pig atria. 2-Fluoro- and 5-fluoroisoproterenol were equipotent with (+/-)-isoproterenol, while 6-fluoroisoprotenol was virtually inactive. No alpha-adrenergic agonist activity (guinea pig aorta) was shown by any of the fluoroisoproterenols. Displacement of alpha- and beta-specific radioligands from isolated membrane preparations from rat brain by the fluoroisoproterenols were in agreement with the responses of the organ preparations. Thus, the apparent fluorine-induced specificity is due to specificity at the receptor binding site. The effects of fluorine substitution are discussed with regard to the apparent negative influence of the 6-fluoro substituent on the beta-agonist properties of isoproterenol, the lack of any increase in potency due to the 2-fluoro substituent, and the possibility of fluorine-induced changes in the electron density of the aromatic ring as a possible rational for the fluorine-induced specificity of both the fluoroisoproterenols and the fluoronoirepinephrines.
|
Agonistic activity for Beta-3 adrenergic receptor as relaxing ability of isolated ferret detrusor basal tone
|
Mustela putorius furo
|
87.1
nM
|
|
Journal : J. Med. Chem.
Title : Relationship between stereochemistry and the beta3-adrenoceptor agonistic activity of 4'-hydroxynorephedrine derivative as an agent for treatment of frequent urination and urinary incontinence.
Year : 2003
Volume : 46
Issue : 1
First Page : 105
Last Page : 112
Authors : Tanaka N, Tamai T, Mukaiyama H, Hirabayashi A, Muranaka H, Ishikawa T, Kobayashi J, Akahane S, Akahane M.
Abstract : This report proposes a beta(3)-adrenoceptor (AR) selective agonist, 2-[2-chloro-4-(2-([(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino)ethyl)phenoxy]acetic acid (1a), as a novel agent for treating urinary bladder dysfunction. This compound and its relatives have a unique feature among beta(3)-AR agonists: two chiral carbons are adjacently structured on the left side of the molecule. To study the relationship between the stereoconfiguration of the vicinal chiral carbons in 1a and beta-AR agonistic activity, the four stereoisomers were synthesized via oxazolidinone prepared by intracyclization involving inversion of the beta-hydroxy group. The in vitro assays using rat atria for beta(1)-AR, rat uteri for beta(2)-AR, and ferret detrusor for beta(3)-AR showed that 1a possessed potent beta(3)-AR agonistic activity (EC(50) = 3.85 nM) and 3700- and 1700-fold selectivity for beta(3)-AR relative to beta(1)- and beta(2)-AR, respectively. Comparison of the four isomers revealed that the (alphaS,betaR)-compound (1a) was not only the most potent agonist but was also the most selective for beta(3)-AR. In the anesthetized rat, intravenous administration of 1a brought about a sufficient decrement of the intrabladder pressure (ED(50) = 12 microg/kg), and intraduodenal administration of 2a, which is the ethyl ester of 1a, led to same result (ED(50) = 0.65 mg/kg). Moreover, no effects on the cardiovascular system were observed in either test.
|
The compound was evaluated for the inhibition of [125I]cyanopindolol binding to beta adrenergic receptor in rat reticulocyte membrane.
|
None
|
325.0
nM
|
|
Journal : J. Med. Chem.
Title : Carbostyril derivatives having potent beta-adrenergic agonist properties.
Year : 1987
Volume : 30
Issue : 9
First Page : 1563
Last Page : 1566
Authors : Milecki J, Baker SP, Standifer KM, Ishizu T, Chida Y, Kusiak JW, Pitha J.
Abstract : Derivatives carrying a substituent in the para position of the phenyl group of 8-hydroxy-5-[2-[(1-phenyl-2-methylprop-2-yl)amino]-1-hydroxyethyl] carbostyril (10) were prepared and their effects on beta-adrenoceptors evaluated in vitro. Unsubstituted compound 10, iodo 11, amino 12, and bromoacetamido 13 derivatives (all racemic) bound to the receptor with 15-100-fold lower dissociation constants than that of (-)-isoproterenol. All the above compounds stimulated adenylate cyclase more potently than (-)-isoproterenol. The intrinsic activities of compounds 10 and 12 were equal to that of (-)-isoproterenol. The intrinsic activities of compounds 11 and 13 were 1.3 and 1.2 times that of (-)-isoproterenol, respectively. Treatment of membrane preparations with bromoacetamido derivative 13 resulted in an irreversible loss of binding sites, and thus, 13 seems to be an alkylating affinity label for beta-adrenoceptors.
|
In vitro beta adrenergic receptor activity against beta-3 adrenergic receptor in rat epididymal fat pads by stimulation of glycerol release from adipocytes.
|
None
|
13.0
nM
|
|
Journal : J. Med. Chem.
Title : Disodium (R,R)-5-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]-amino] propyl]-1,3-benzodioxole-2,2-dicarboxylate (CL 316,243). A potent beta-adrenergic agonist virtually specific for beta 3 receptors. A promising antidiabetic and antiobesity agent.
Year : 1992
Volume : 35
Issue : 16
First Page : 3081
Last Page : 3084
Authors : Bloom JD, Dutia MD, Johnson BD, Wissner A, Burns MG, Largis EE, Dolan JA, Claus TH.
|
Agonistic activity (beta-1 adrenergic receptor) for the percent maximal increase in contraction rate of isolated guinea pig atria
|
Cavia porcellus
|
6.0
nM
|
|
Journal : J. Med. Chem.
Title : Effect of fluorine substitution on the adrenergic properties of 3-(tert-butylamino)-1-(3,4-dihydroxyphenoxy)-2-propanol.
Year : 1991
Volume : 34
Issue : 3
First Page : 1063
Last Page : 1068
Authors : Adejare A, Nie JY, Hebel D, Brackett LE, Choi O, Gusovsky F, Padgett WL, Daly JW, Creveling CR, Kirk KL.
Abstract : The 2- and 6-fluoro derivatives of the potent beta-adrenergic agonist 3-(tert-butylamino)-1-(3,4-dihydroxyphenoxy)-2-propanol were prepared and their adrenergic properties examined. The order of potency was as follows: beta-adrenergic activity (simulation of cyclic AMP formation in C6 glioma cells), 2-F = parent much greater than 6-F; beta 1-activity (rate of contraction, guinea pig atria), parent greater than 2-F much greater than 6-F; beta 2-activity (relaxation of guinea pig tracheal strip), 2-F greater than parent much greater than 6-F. The affinity of the 2-fluoro analogue for beta 1-adrenergic receptors (inhibition of the specific binding of [3H]dihydroalprenolol, rat cerebral cortical membranes) was 2 times greater, while the 6-fluoro analogue was 1450 times less than the parent. These results suggest that the aromatic rings of phenoxypropanolamine adrenergic agonists and phenylethanolamine adrenergic agonists bind in similar fashion to the adrenergic receptor, and that if interactions between fluorine and the side-chain hydroxyl group are critical in defining beta-adrenergic selectivity, the interactions are similar in both phenoxypropanolamines and phenylethanolamines.
|
Activity against human beta 1 adrenergic receptor (AR), expressed in CHO cells.
|
None
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and evaluation of potent and selective beta(3) adrenergic receptor agonists containing acylsulfonamide, sulfonylsulfonamide, and sulfonylurea carboxylic acid isosteres.
Year : 2002
Volume : 45
Issue : 3
First Page : 567
Last Page : 583
Authors : Uehling DE, Donaldson KH, Deaton DN, Hyman CE, Sugg EE, Barrett DG, Hughes RG, Reitter B, Adkison KK, Lancaster ME, Lee F, Hart R, Paulik MA, Sherman BW, True T, Cowan C.
Abstract : Starting from phenethanolamine aniline leads 3a and 3b, we have identified a series of functionally potent and selective beta(3) adrenergic receptor (AR) agonists containing acylsulfonamide, sulfonylsulfonamide, or sulfonylurea groups within the aniline phenethanolamine series. In beta(3), beta(2), and beta(1) AR cAMP functional assays, 3a and other right-hand side (RHS) carboxylate analogues were found to be full agonists that were modestly selective against beta(1) or beta(2) ARs, while analogues lacking RHS acid functionality were active at beta(3) AR but not selective. Replacement of the carboxylate with acylthiazole and acylmethylsulfone gave potent, but only modestly selective, compounds. Increasing the size of the RHS sulfonamide substituent with phenyl or p-toluene afforded compounds with good potency and functional selectivity (beta(3) AR pEC(50) greater than 8; beta(1) and beta(2) AR selectivity greater than 40- and 500-fold, respectively). Our SAR studies suggest that the potency and selectivity profile of the best analogues reported here is a result of both the steric bulk and acidity of the RHS sulfonamide NH group. Although all of the analogues had a pharmacokinetic half-life of less than 2 h, acylsulfonamides 43 and 44 did show moderately low clearance in dogs. These two compounds were further evaluated by thermographic imaging in mice and were found to produce a robust thermogenic response via oral administration.
|
Activity against human beta 2 adrenergic receptor (AR), expressed in CHO cells
|
None
|
0.1585
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and evaluation of potent and selective beta(3) adrenergic receptor agonists containing acylsulfonamide, sulfonylsulfonamide, and sulfonylurea carboxylic acid isosteres.
Year : 2002
Volume : 45
Issue : 3
First Page : 567
Last Page : 583
Authors : Uehling DE, Donaldson KH, Deaton DN, Hyman CE, Sugg EE, Barrett DG, Hughes RG, Reitter B, Adkison KK, Lancaster ME, Lee F, Hart R, Paulik MA, Sherman BW, True T, Cowan C.
Abstract : Starting from phenethanolamine aniline leads 3a and 3b, we have identified a series of functionally potent and selective beta(3) adrenergic receptor (AR) agonists containing acylsulfonamide, sulfonylsulfonamide, or sulfonylurea groups within the aniline phenethanolamine series. In beta(3), beta(2), and beta(1) AR cAMP functional assays, 3a and other right-hand side (RHS) carboxylate analogues were found to be full agonists that were modestly selective against beta(1) or beta(2) ARs, while analogues lacking RHS acid functionality were active at beta(3) AR but not selective. Replacement of the carboxylate with acylthiazole and acylmethylsulfone gave potent, but only modestly selective, compounds. Increasing the size of the RHS sulfonamide substituent with phenyl or p-toluene afforded compounds with good potency and functional selectivity (beta(3) AR pEC(50) greater than 8; beta(1) and beta(2) AR selectivity greater than 40- and 500-fold, respectively). Our SAR studies suggest that the potency and selectivity profile of the best analogues reported here is a result of both the steric bulk and acidity of the RHS sulfonamide NH group. Although all of the analogues had a pharmacokinetic half-life of less than 2 h, acylsulfonamides 43 and 44 did show moderately low clearance in dogs. These two compounds were further evaluated by thermographic imaging in mice and were found to produce a robust thermogenic response via oral administration.
|
Agonistic activity (beta2- adrenergic) for the percent maximal relaxation of isolated guinea pig trachea
|
Cavia porcellus
|
58.0
nM
|
|
Journal : J. Med. Chem.
Title : Effect of fluorine substitution on the adrenergic properties of 3-(tert-butylamino)-1-(3,4-dihydroxyphenoxy)-2-propanol.
Year : 1991
Volume : 34
Issue : 3
First Page : 1063
Last Page : 1068
Authors : Adejare A, Nie JY, Hebel D, Brackett LE, Choi O, Gusovsky F, Padgett WL, Daly JW, Creveling CR, Kirk KL.
Abstract : The 2- and 6-fluoro derivatives of the potent beta-adrenergic agonist 3-(tert-butylamino)-1-(3,4-dihydroxyphenoxy)-2-propanol were prepared and their adrenergic properties examined. The order of potency was as follows: beta-adrenergic activity (simulation of cyclic AMP formation in C6 glioma cells), 2-F = parent much greater than 6-F; beta 1-activity (rate of contraction, guinea pig atria), parent greater than 2-F much greater than 6-F; beta 2-activity (relaxation of guinea pig tracheal strip), 2-F greater than parent much greater than 6-F. The affinity of the 2-fluoro analogue for beta 1-adrenergic receptors (inhibition of the specific binding of [3H]dihydroalprenolol, rat cerebral cortical membranes) was 2 times greater, while the 6-fluoro analogue was 1450 times less than the parent. These results suggest that the aromatic rings of phenoxypropanolamine adrenergic agonists and phenylethanolamine adrenergic agonists bind in similar fashion to the adrenergic receptor, and that if interactions between fluorine and the side-chain hydroxyl group are critical in defining beta-adrenergic selectivity, the interactions are similar in both phenoxypropanolamines and phenylethanolamines.
|
Activity against human beta 3 adrenergic receptor (AR), expressed in CHO cells.
|
None
|
3.162
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and evaluation of potent and selective beta(3) adrenergic receptor agonists containing acylsulfonamide, sulfonylsulfonamide, and sulfonylurea carboxylic acid isosteres.
Year : 2002
Volume : 45
Issue : 3
First Page : 567
Last Page : 583
Authors : Uehling DE, Donaldson KH, Deaton DN, Hyman CE, Sugg EE, Barrett DG, Hughes RG, Reitter B, Adkison KK, Lancaster ME, Lee F, Hart R, Paulik MA, Sherman BW, True T, Cowan C.
Abstract : Starting from phenethanolamine aniline leads 3a and 3b, we have identified a series of functionally potent and selective beta(3) adrenergic receptor (AR) agonists containing acylsulfonamide, sulfonylsulfonamide, or sulfonylurea groups within the aniline phenethanolamine series. In beta(3), beta(2), and beta(1) AR cAMP functional assays, 3a and other right-hand side (RHS) carboxylate analogues were found to be full agonists that were modestly selective against beta(1) or beta(2) ARs, while analogues lacking RHS acid functionality were active at beta(3) AR but not selective. Replacement of the carboxylate with acylthiazole and acylmethylsulfone gave potent, but only modestly selective, compounds. Increasing the size of the RHS sulfonamide substituent with phenyl or p-toluene afforded compounds with good potency and functional selectivity (beta(3) AR pEC(50) greater than 8; beta(1) and beta(2) AR selectivity greater than 40- and 500-fold, respectively). Our SAR studies suggest that the potency and selectivity profile of the best analogues reported here is a result of both the steric bulk and acidity of the RHS sulfonamide NH group. Although all of the analogues had a pharmacokinetic half-life of less than 2 h, acylsulfonamides 43 and 44 did show moderately low clearance in dogs. These two compounds were further evaluated by thermographic imaging in mice and were found to produce a robust thermogenic response via oral administration.
|
Effective concentration for increasing potency force in guinea pig isolated left atria
|
Cavia porcellus
|
3.2
nM
|
|
Journal : J. Med. Chem.
Title : N-Aralkyl substitution of 2-amino-5,6- and -6,7-dihydroxy-1,2,3,4-tetrahydronaphthalenes. 1. Cardiac and pressor/depressor activities.
Year : 1981
Volume : 24
Issue : 7
First Page : 835
Last Page : 839
Authors : Gorczynski RJ, Anderson WG, Stout DM.
Abstract : Amino substitution o rigid forms of dopamine [2-amino-5,6-dihydroxy-1,2,3,4-tetrahydronaphthalene (A-5,6-DTN) and 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (A-6,7-DTN)] with aralkyl functionalities was carried out to investigate the role of such structural modifications upon cardiac inotropic/chronotropic and blood pressure activity. Derivatives of A-5,6-DTN were strong vasodepressor agents devoid action was associated with the dihydroxyphenyl-1-methylethyl derivative, which was also an inotropic selective compound. The amino substituent of dobutamine was ineffective in reducing peripheral vascular action when combined with the rigid forms of dopamine. It was also ineffective in imparting inotropic selectivity when combined with A-5,6-DTN. An analysis of these observations in light of existing structure-activity relationships of aminoaralkyl substitution of other catecholamine structure is presented.
|
Effective concentration for increasing potency rate in guinea pig isolated right atria
|
Cavia porcellus
|
6.2
nM
|
|
Journal : J. Med. Chem.
Title : N-Aralkyl substitution of 2-amino-5,6- and -6,7-dihydroxy-1,2,3,4-tetrahydronaphthalenes. 1. Cardiac and pressor/depressor activities.
Year : 1981
Volume : 24
Issue : 7
First Page : 835
Last Page : 839
Authors : Gorczynski RJ, Anderson WG, Stout DM.
Abstract : Amino substitution o rigid forms of dopamine [2-amino-5,6-dihydroxy-1,2,3,4-tetrahydronaphthalene (A-5,6-DTN) and 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (A-6,7-DTN)] with aralkyl functionalities was carried out to investigate the role of such structural modifications upon cardiac inotropic/chronotropic and blood pressure activity. Derivatives of A-5,6-DTN were strong vasodepressor agents devoid action was associated with the dihydroxyphenyl-1-methylethyl derivative, which was also an inotropic selective compound. The amino substituent of dobutamine was ineffective in reducing peripheral vascular action when combined with the rigid forms of dopamine. It was also ineffective in imparting inotropic selectivity when combined with A-5,6-DTN. An analysis of these observations in light of existing structure-activity relationships of aminoaralkyl substitution of other catecholamine structure is presented.
|
Compound was evaluated in vitro by SDT (Schultz-Dale Test) against isolated guinea pig lung strips repeatedly challenged with antigen in the presence of an antihistamine (H1) at a concentration 30 uM.
|
Cavia porcellus
|
150.0
nM
|
|
Journal : J. Med. Chem.
Title : Acidic furo[3,2-b]indoles. A new series of potent antiallergy agents.
Year : 1984
Volume : 27
Issue : 12
First Page : 1629
Last Page : 1633
Authors : Unangst PC, Carethers ME, Webster K, Janik GM, Robichaud LJ.
Abstract : A series of furo[3,2-b]indole carboxylic acids, tetrazoles, and carbamoyltetrazoles was prepared and tested in vitro with use of a model of active pulmonary anaphylaxis, the modified Schultz-Dale Test (SDT). In this model, isolated guinea pig lung strips are repeatedly challenged with antigen in the presence of an antihistamine (H1). Most of the acidic furo[3,2-b]indoles tested inhibited the leukotriene-mediated lung contraction in a dose-related manner. Compounds with an N-phenyl substituent were more potent (IC50 less than or equal to 5.0 microM) inhibitors of SDT than the N-methyl analogues (IC50 greater than or equal to 22.0 microM). Most of the N-phenyl analogues were more potent in SDT than Fisons' mediator-release inhibitor proxicromil (FPL-57,787; IC50 = 6.3 microM). The most potent furo[3,2-b]indoles were those unsubstituted at C-7 and with N-phenyl, 2-carbamoyltetrazole, and 3-alkoxy substituents. All of the carboxylic acid ester analogues tested were weak or inactive at concentrations of 10-30 microM.
|
In vitro concentration required to produce 50% relaxation of rat detrusor
|
Rattus norvegicus
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of novel N-phenylglycine derivatives as potent and selective beta(3)-adrenoceptor agonists for the treatment of frequent urination and urinary incontinence.
Year : 2001
Volume : 44
Issue : 9
First Page : 1436
Last Page : 1445
Authors : Tanaka N, Tamai T, Mukaiyama H, Hirabayashi A, Muranaka H, Akahane S, Miyata H, Akahane M.
Abstract : With a novel assay using isolated ferret detrusor to estimate beta(3)-adrenoceptor agonistic activity, we found that a series of glycine derivatives of ritodrine, a beta(2)-adrenoceptor agonist, are potent beta(3)-adrenoceptor agonists, with excellent selectivity versus beta(1) and beta(2) subtypes. Substitution of halogens in the phenyl ring increased potency and selectivity for the beta(3)-adrenoceptor, and this was dependent upon the position of the halogens. The chlorine-substituted derivatives 3f-i exhibited potent beta(3)-adrenoceptor-mediated relaxation of ferret detrusor (EC(50) = 0.93, 11, 14, and 160 nM) and higher potency at beta(3)-adrenoceptors than at beta(1) or beta(2). The intravenous administration of 3h significantly reduced the urinary bladder pressure in anesthetized male rats (ED(50) = 48 microg/kg) without cardiovascular side effects. This article is the first report of structure-activity relationships (SAR) concerning beta(3)-adrenoceptor agonists as agents for the treatment of urinary frequency and incontinence.
|
The compound was evaluated for its ability to stimulate adenylate cyclase activity
|
Rattus norvegicus
|
226.0
nM
|
|
Journal : J. Med. Chem.
Title : Carbostyril derivatives having potent beta-adrenergic agonist properties.
Year : 1987
Volume : 30
Issue : 9
First Page : 1563
Last Page : 1566
Authors : Milecki J, Baker SP, Standifer KM, Ishizu T, Chida Y, Kusiak JW, Pitha J.
Abstract : Derivatives carrying a substituent in the para position of the phenyl group of 8-hydroxy-5-[2-[(1-phenyl-2-methylprop-2-yl)amino]-1-hydroxyethyl] carbostyril (10) were prepared and their effects on beta-adrenoceptors evaluated in vitro. Unsubstituted compound 10, iodo 11, amino 12, and bromoacetamido 13 derivatives (all racemic) bound to the receptor with 15-100-fold lower dissociation constants than that of (-)-isoproterenol. All the above compounds stimulated adenylate cyclase more potently than (-)-isoproterenol. The intrinsic activities of compounds 10 and 12 were equal to that of (-)-isoproterenol. The intrinsic activities of compounds 11 and 13 were 1.3 and 1.2 times that of (-)-isoproterenol, respectively. Treatment of membrane preparations with bromoacetamido derivative 13 resulted in an irreversible loss of binding sites, and thus, 13 seems to be an alkylating affinity label for beta-adrenoceptors.
|
KD constant value was evaluated for the displacement of ICYP (iodocyanopindolol) binding in SF-49 lymphoma cell
|
Mus musculus
|
9.8e-07
|
|
Journal : J. Med. Chem.
Title : Conjugates of catecholamines. 5. Synthesis and beta-adrenergic activity of N-(aminoalkyl)norepinephrine derivatives.
Year : 1985
Volume : 28
Issue : 5
First Page : 634
Last Page : 642
Authors : Reitz AB, Sonveaux E, Rosenkranz RP, Verlander MS, Melmon KL, Hoffman BB, Akita Y, Castagnoli N, Goodman M.
Abstract : A novel series of N-aminoalkyl congeners and model derivatives of norepinephrine has been synthesized. Compounds that were structurally related to epinephrine were prepared from fully protected intermediates. Alternatively, isoproterenol-related compounds were synthesized via reductive amination of preformed methyl ketone derivatives with norepinephrine. The beta-adrenergic activities of these new compounds were assessed through measurement of intracellular cyclic AMP accumulation in S49 mouse lymphoma cells and displacement of iodocyanopindolol (ICYP) from membrane preparations. Congeners that contained an underivatized primary amine function exhibited virtually no activity in these assays. However, when this amine function was acylated (e.g., to an amide, carbamate, urea, sulfonamide, etc.), the products exhibited generally increased beta-adrenergic activity, which was, however, strongly dependent on the nature of the acylating group and also the length of the spacer. In particular, a benzyl carbamate derivative containing a branched, seven-carbon spacer group was 40 times more potent than isoproterenol in the in vitro S49 assay.
|
Compound is tested for EC50, the mean concentration required to produce 50% relaxation of ferret detrusor in vitro
|
Mustela putorius furo
|
87.1
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of novel N-phenylglycine derivatives as potent and selective beta(3)-adrenoceptor agonists for the treatment of frequent urination and urinary incontinence.
Year : 2001
Volume : 44
Issue : 9
First Page : 1436
Last Page : 1445
Authors : Tanaka N, Tamai T, Mukaiyama H, Hirabayashi A, Muranaka H, Akahane S, Miyata H, Akahane M.
Abstract : With a novel assay using isolated ferret detrusor to estimate beta(3)-adrenoceptor agonistic activity, we found that a series of glycine derivatives of ritodrine, a beta(2)-adrenoceptor agonist, are potent beta(3)-adrenoceptor agonists, with excellent selectivity versus beta(1) and beta(2) subtypes. Substitution of halogens in the phenyl ring increased potency and selectivity for the beta(3)-adrenoceptor, and this was dependent upon the position of the halogens. The chlorine-substituted derivatives 3f-i exhibited potent beta(3)-adrenoceptor-mediated relaxation of ferret detrusor (EC(50) = 0.93, 11, 14, and 160 nM) and higher potency at beta(3)-adrenoceptors than at beta(1) or beta(2). The intravenous administration of 3h significantly reduced the urinary bladder pressure in anesthetized male rats (ED(50) = 48 microg/kg) without cardiovascular side effects. This article is the first report of structure-activity relationships (SAR) concerning beta(3)-adrenoceptor agonists as agents for the treatment of urinary frequency and incontinence.
|
In vitro beta-adrenergic activity against beta-1 adrenergic receptor by stimulation of rate of contraction of guinea pig atria
|
Cavia porcellus
|
1.5
nM
|
|
Journal : J. Med. Chem.
Title : Disodium (R,R)-5-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]-amino] propyl]-1,3-benzodioxole-2,2-dicarboxylate (CL 316,243). A potent beta-adrenergic agonist virtually specific for beta 3 receptors. A promising antidiabetic and antiobesity agent.
Year : 1992
Volume : 35
Issue : 16
First Page : 3081
Last Page : 3084
Authors : Bloom JD, Dutia MD, Johnson BD, Wissner A, Burns MG, Largis EE, Dolan JA, Claus TH.
|
In vitro beta-adrenergic activity against beta-1 adrenergic receptor by the inhibition of insulin stimulated [14C]- glucose incorporation into glycogen in isolated rat soleus muscle
|
None
|
5.3
nM
|
|
Journal : J. Med. Chem.
Title : Disodium (R,R)-5-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]-amino] propyl]-1,3-benzodioxole-2,2-dicarboxylate (CL 316,243). A potent beta-adrenergic agonist virtually specific for beta 3 receptors. A promising antidiabetic and antiobesity agent.
Year : 1992
Volume : 35
Issue : 16
First Page : 3081
Last Page : 3084
Authors : Bloom JD, Dutia MD, Johnson BD, Wissner A, Burns MG, Largis EE, Dolan JA, Claus TH.
|
Agonistic activity towards beta-2 adrenoceptor. IC50, the mean concentration required to produce 50% inhibition of uterine contraction
|
None
|
0.1
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of novel N-phenylglycine derivatives as potent and selective beta(3)-adrenoceptor agonists for the treatment of frequent urination and urinary incontinence.
Year : 2001
Volume : 44
Issue : 9
First Page : 1436
Last Page : 1445
Authors : Tanaka N, Tamai T, Mukaiyama H, Hirabayashi A, Muranaka H, Akahane S, Miyata H, Akahane M.
Abstract : With a novel assay using isolated ferret detrusor to estimate beta(3)-adrenoceptor agonistic activity, we found that a series of glycine derivatives of ritodrine, a beta(2)-adrenoceptor agonist, are potent beta(3)-adrenoceptor agonists, with excellent selectivity versus beta(1) and beta(2) subtypes. Substitution of halogens in the phenyl ring increased potency and selectivity for the beta(3)-adrenoceptor, and this was dependent upon the position of the halogens. The chlorine-substituted derivatives 3f-i exhibited potent beta(3)-adrenoceptor-mediated relaxation of ferret detrusor (EC(50) = 0.93, 11, 14, and 160 nM) and higher potency at beta(3)-adrenoceptors than at beta(1) or beta(2). The intravenous administration of 3h significantly reduced the urinary bladder pressure in anesthetized male rats (ED(50) = 48 microg/kg) without cardiovascular side effects. This article is the first report of structure-activity relationships (SAR) concerning beta(3)-adrenoceptor agonists as agents for the treatment of urinary frequency and incontinence.
|
Agonistic activity towards beta-3 adrenoceptor. EC50, the mean concentration required to produce 50% relaxation of detrusor before the addition in the ferret detrusor
|
None
|
87.1
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of novel N-phenylglycine derivatives as potent and selective beta(3)-adrenoceptor agonists for the treatment of frequent urination and urinary incontinence.
Year : 2001
Volume : 44
Issue : 9
First Page : 1436
Last Page : 1445
Authors : Tanaka N, Tamai T, Mukaiyama H, Hirabayashi A, Muranaka H, Akahane S, Miyata H, Akahane M.
Abstract : With a novel assay using isolated ferret detrusor to estimate beta(3)-adrenoceptor agonistic activity, we found that a series of glycine derivatives of ritodrine, a beta(2)-adrenoceptor agonist, are potent beta(3)-adrenoceptor agonists, with excellent selectivity versus beta(1) and beta(2) subtypes. Substitution of halogens in the phenyl ring increased potency and selectivity for the beta(3)-adrenoceptor, and this was dependent upon the position of the halogens. The chlorine-substituted derivatives 3f-i exhibited potent beta(3)-adrenoceptor-mediated relaxation of ferret detrusor (EC(50) = 0.93, 11, 14, and 160 nM) and higher potency at beta(3)-adrenoceptors than at beta(1) or beta(2). The intravenous administration of 3h significantly reduced the urinary bladder pressure in anesthetized male rats (ED(50) = 48 microg/kg) without cardiovascular side effects. This article is the first report of structure-activity relationships (SAR) concerning beta(3)-adrenoceptor agonists as agents for the treatment of urinary frequency and incontinence.
|
Agonistic activity was assessed by measuring cAMP accumulation in CHO cell lines expressing cloned human Beta-1 adrenergic receptor
|
None
|
0.084
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of a novel, potent and selective human beta3-adrenergic receptor agonist.
Year : 2005
Volume : 15
Issue : 2
First Page : 251
Last Page : 254
Authors : Nakajima Y, Hamashima H, Washizuka K, Tomishima Y, Ohtake H, Imamura E, Miura T, Kayakiri H, Kato M.
Abstract : The discovery of a novel, potent and selective beta(3)-adrenergic receptor (AR) agonist is described. SAR studies demonstrated the structural requirements for activity and selectivity. Compound 1c, which showed good beta(3)-AR activity and selectivity, was identified and pharmacokinetics were investigated.
|
Agonistic activity was assessed by measuring cAMP accumulation in CHO cell lines expressing cloned human Beta-2 adrenergic receptor
|
Homo sapiens
|
2.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of a novel, potent and selective human beta3-adrenergic receptor agonist.
Year : 2005
Volume : 15
Issue : 2
First Page : 251
Last Page : 254
Authors : Nakajima Y, Hamashima H, Washizuka K, Tomishima Y, Ohtake H, Imamura E, Miura T, Kayakiri H, Kato M.
Abstract : The discovery of a novel, potent and selective beta(3)-adrenergic receptor (AR) agonist is described. SAR studies demonstrated the structural requirements for activity and selectivity. Compound 1c, which showed good beta(3)-AR activity and selectivity, was identified and pharmacokinetics were investigated.
|
Agonistic activity was assessed by measuring cAMP accumulation in CHO cell lines expressing cloned human Beta-3 adrenergic receptor
|
None
|
0.97
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of a novel, potent and selective human beta3-adrenergic receptor agonist.
Year : 2005
Volume : 15
Issue : 2
First Page : 251
Last Page : 254
Authors : Nakajima Y, Hamashima H, Washizuka K, Tomishima Y, Ohtake H, Imamura E, Miura T, Kayakiri H, Kato M.
Abstract : The discovery of a novel, potent and selective beta(3)-adrenergic receptor (AR) agonist is described. SAR studies demonstrated the structural requirements for activity and selectivity. Compound 1c, which showed good beta(3)-AR activity and selectivity, was identified and pharmacokinetics were investigated.
|
Activity at human beta-3 adrenergic receptor expressed in CHO cells by stimulation of cAMP production
|
Homo sapiens
|
3.162
nM
|
|
Journal : J. Med. Chem.
Title : Biarylaniline phenethanolamines as potent and selective beta3 adrenergic receptor agonists.
Year : 2006
Volume : 49
Issue : 9
First Page : 2758
Last Page : 2771
Authors : Uehling DE, Shearer BG, Donaldson KH, Chao EY, Deaton DN, Adkison KK, Brown KK, Cariello NF, Faison WL, Lancaster ME, Lin J, Hart R, Milliken TO, Paulik MA, Sherman BW, Sugg EE, Cowan C.
Abstract : The synthesis of a series of phenethanolamine aniline agonists that contain an aniline ring on the right-hand side of the molecule substituted at the meta position with a benzoic acid or a pyridyl carboxylate is described. Several of the analogues (e.g., 34, 36-38, 40, and 44) have high beta(3) adrenergic receptor (AR) potency and selectivity against beta(1) and beta(2) ARs in Chinese hamster ovary (CHO) cells expressing beta ARs. The dog pharmacokinetic profile of some of these analogues showed >25% oral bioavailability and po half-lives of at least 1.5 h. Among the compounds described herein, the 3,3'-biarylaniline carboxylate derivatives 36, 38 and the phenylpyridyl derivative 44 demonstrated outstanding in vitro properties and reasonable dog pharmacokinetic profiles. These three analogues also showed dose dependent beta(3) AR mediated responses in mice. The ease of synthesis and superior dog pharmacokinetics of compound 38 relative to that of 44 in combination with its in vitro profile led us to choose this compound as a development candidate for the treatment of type 2 diabetes.
|
Activity at human beta-2 adrenergic receptor expressed in CHO cells by stimulation of cAMP production
|
Homo sapiens
|
0.1585
nM
|
|
Journal : J. Med. Chem.
Title : Biarylaniline phenethanolamines as potent and selective beta3 adrenergic receptor agonists.
Year : 2006
Volume : 49
Issue : 9
First Page : 2758
Last Page : 2771
Authors : Uehling DE, Shearer BG, Donaldson KH, Chao EY, Deaton DN, Adkison KK, Brown KK, Cariello NF, Faison WL, Lancaster ME, Lin J, Hart R, Milliken TO, Paulik MA, Sherman BW, Sugg EE, Cowan C.
Abstract : The synthesis of a series of phenethanolamine aniline agonists that contain an aniline ring on the right-hand side of the molecule substituted at the meta position with a benzoic acid or a pyridyl carboxylate is described. Several of the analogues (e.g., 34, 36-38, 40, and 44) have high beta(3) adrenergic receptor (AR) potency and selectivity against beta(1) and beta(2) ARs in Chinese hamster ovary (CHO) cells expressing beta ARs. The dog pharmacokinetic profile of some of these analogues showed >25% oral bioavailability and po half-lives of at least 1.5 h. Among the compounds described herein, the 3,3'-biarylaniline carboxylate derivatives 36, 38 and the phenylpyridyl derivative 44 demonstrated outstanding in vitro properties and reasonable dog pharmacokinetic profiles. These three analogues also showed dose dependent beta(3) AR mediated responses in mice. The ease of synthesis and superior dog pharmacokinetics of compound 38 relative to that of 44 in combination with its in vitro profile led us to choose this compound as a development candidate for the treatment of type 2 diabetes.
|
Activity at human beta-1 adrenergic receptor expressed in CHO cells by stimulation of cAMP production
|
Homo sapiens
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : Biarylaniline phenethanolamines as potent and selective beta3 adrenergic receptor agonists.
Year : 2006
Volume : 49
Issue : 9
First Page : 2758
Last Page : 2771
Authors : Uehling DE, Shearer BG, Donaldson KH, Chao EY, Deaton DN, Adkison KK, Brown KK, Cariello NF, Faison WL, Lancaster ME, Lin J, Hart R, Milliken TO, Paulik MA, Sherman BW, Sugg EE, Cowan C.
Abstract : The synthesis of a series of phenethanolamine aniline agonists that contain an aniline ring on the right-hand side of the molecule substituted at the meta position with a benzoic acid or a pyridyl carboxylate is described. Several of the analogues (e.g., 34, 36-38, 40, and 44) have high beta(3) adrenergic receptor (AR) potency and selectivity against beta(1) and beta(2) ARs in Chinese hamster ovary (CHO) cells expressing beta ARs. The dog pharmacokinetic profile of some of these analogues showed >25% oral bioavailability and po half-lives of at least 1.5 h. Among the compounds described herein, the 3,3'-biarylaniline carboxylate derivatives 36, 38 and the phenylpyridyl derivative 44 demonstrated outstanding in vitro properties and reasonable dog pharmacokinetic profiles. These three analogues also showed dose dependent beta(3) AR mediated responses in mice. The ease of synthesis and superior dog pharmacokinetics of compound 38 relative to that of 44 in combination with its in vitro profile led us to choose this compound as a development candidate for the treatment of type 2 diabetes.
|
Agonist activity at human beta3 adrenergic receptor expressed in CHO cells assessed as cAMP accumulation by EIA
|
Homo sapiens
|
0.97
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of a novel series of biphenyl benzoic acid derivatives as potent and selective human beta3-adrenergic receptor agonists with good oral bioavailability. Part I.
Year : 2008
Volume : 51
Issue : 6
First Page : 1925
Last Page : 1944
Authors : Imanishi M, Tomishima Y, Itou S, Hamashima H, Nakajima Y, Washizuka K, Sakurai M, Matsui S, Imamura E, Ueshima K, Yamamoto T, Yamamoto N, Ishikawa H, Nakano K, Unami N, Hamada K, Matsumura Y, Takamura F, Hattori K.
Abstract : A novel class of biphenyl analogues containing a benzoic acid moiety based on lead compound 8i have been identified as potent and selective human beta 3 adrenergic receptor (beta 3-AR) agonists with good oral bioavailability and long plasma half-life. After further substituent effects were investigated at the terminal phenyl ring of lead compound 8i, we have discovered that more lipophilic substitution at the R position improved potency and selectivity. As a result of these studies, 10a and 10e were identified as the leading candidates with the best balance of potency, selectivity, and pharmacokinetic profiles. In addition, compounds 10a and 10e were evaluated to be efficacious for a carbachol-induced increase of intravesical pressure, such as an overactive bladder model in anesthetized dogs. This represents the first demonstrated result dealing with beta 3-AR agonists.
|
Agonist activity at human beta-1 adrenergic receptor expressed in CHO cells assessed as cAMP accumulation by EIA
|
Homo sapiens
|
0.084
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of a novel series of biphenyl benzoic acid derivatives as potent and selective human beta3-adrenergic receptor agonists with good oral bioavailability. Part I.
Year : 2008
Volume : 51
Issue : 6
First Page : 1925
Last Page : 1944
Authors : Imanishi M, Tomishima Y, Itou S, Hamashima H, Nakajima Y, Washizuka K, Sakurai M, Matsui S, Imamura E, Ueshima K, Yamamoto T, Yamamoto N, Ishikawa H, Nakano K, Unami N, Hamada K, Matsumura Y, Takamura F, Hattori K.
Abstract : A novel class of biphenyl analogues containing a benzoic acid moiety based on lead compound 8i have been identified as potent and selective human beta 3 adrenergic receptor (beta 3-AR) agonists with good oral bioavailability and long plasma half-life. After further substituent effects were investigated at the terminal phenyl ring of lead compound 8i, we have discovered that more lipophilic substitution at the R position improved potency and selectivity. As a result of these studies, 10a and 10e were identified as the leading candidates with the best balance of potency, selectivity, and pharmacokinetic profiles. In addition, compounds 10a and 10e were evaluated to be efficacious for a carbachol-induced increase of intravesical pressure, such as an overactive bladder model in anesthetized dogs. This represents the first demonstrated result dealing with beta 3-AR agonists.
|
Agonist activity at human adrenergic beta-3 receptor expressed in CHO cells assessed as cAMP levels by DELFIA method
|
Homo sapiens
|
5.8
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Stereospecific synthesis and bio-activity of novel beta(3)-adrenoceptor agonists and inverse agonists.
Year : 2008
Volume : 16
Issue : 5
First Page : 2473
Last Page : 2488
Authors : Perrone MG, Santandrea E, Bleve L, Vitale P, Colabufo NA, Jockers R, Milazzo FM, Sciarroni AF, Scilimati A.
Abstract : Since it is widely distributed into the body, beta(3)-adrenoceptor is becoming an attractive target for the treatment of several pathologies such as obesity, type 2 diabetes, metabolic syndrome, cachexia, overactive bladder, ulcero-inflammatory disorder of the gut, preterm labour, anxiety and depressive disorders, and heart failure. New compounds belonging to the class of arylethanolamines bearing one or two stereogenic centres were prepared in good yields as racemates and optically active forms. They were, then, evaluated for their intrinsic activity towards beta(3)-adrenoceptor and their affinity for beta(1)- and beta(2)-adrenergic receptors. Stereochemical features were found to play a crucial role in determining the behaviour of such compounds. In particular, alpha-racemic, (alphaR)- and (alphaS)-2-{4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenoxy}-2- methylpropanoic acid, (alpha-rac, beta-rac)-, (alphaR, betaS)- and (alphaR, betaR)- 2-{4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenoxy}propanoic acid were found to be endowed with beta(3)-adrenoceptor agonistic activity. Whereas, (alphaS, betaS)- and (alphaS, betaR)-2-{4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenoxy}propanoic acid behaved as beta(3)-adrenoceptor inverse agonists. Such compounds showed no affinity for beta(1)- and beta(2)-adrenergic receptor, respectively. Thus, resulting highly selective beta(3)-adrenoceptor ligands.
|
Agonist activity at human adrenergic beta3 receptor expressed in CHO cells assessed as [3H]cAMP levels by radiolabeled ligand based assay
|
Homo sapiens
|
3.9
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Stereospecific synthesis and bio-activity of novel beta(3)-adrenoceptor agonists and inverse agonists.
Year : 2008
Volume : 16
Issue : 5
First Page : 2473
Last Page : 2488
Authors : Perrone MG, Santandrea E, Bleve L, Vitale P, Colabufo NA, Jockers R, Milazzo FM, Sciarroni AF, Scilimati A.
Abstract : Since it is widely distributed into the body, beta(3)-adrenoceptor is becoming an attractive target for the treatment of several pathologies such as obesity, type 2 diabetes, metabolic syndrome, cachexia, overactive bladder, ulcero-inflammatory disorder of the gut, preterm labour, anxiety and depressive disorders, and heart failure. New compounds belonging to the class of arylethanolamines bearing one or two stereogenic centres were prepared in good yields as racemates and optically active forms. They were, then, evaluated for their intrinsic activity towards beta(3)-adrenoceptor and their affinity for beta(1)- and beta(2)-adrenergic receptors. Stereochemical features were found to play a crucial role in determining the behaviour of such compounds. In particular, alpha-racemic, (alphaR)- and (alphaS)-2-{4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenoxy}-2- methylpropanoic acid, (alpha-rac, beta-rac)-, (alphaR, betaS)- and (alphaR, betaR)- 2-{4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenoxy}propanoic acid were found to be endowed with beta(3)-adrenoceptor agonistic activity. Whereas, (alphaS, betaS)- and (alphaS, betaR)-2-{4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenoxy}propanoic acid behaved as beta(3)-adrenoceptor inverse agonists. Such compounds showed no affinity for beta(1)- and beta(2)-adrenergic receptor, respectively. Thus, resulting highly selective beta(3)-adrenoceptor ligands.
|
Agonist activity at human recombinant beta-1 adrenergic receptor expressed in CHO cells assessed as cAMP accumulation by enzyme immuno assay
|
Homo sapiens
|
0.084
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of a novel series of biphenyl benzoic acid derivatives as highly potent and selective human beta3 adrenergic receptor agonists with good oral bioavailability. Part II.
Year : 2008
Volume : 51
Issue : 13
First Page : 4002
Last Page : 4020
Authors : Imanishi M, Itou S, Washizuka K, Hamashima H, Nakajima Y, Araki T, Tomishima Y, Sakurai M, Matsui S, Imamura E, Ueshima K, Yamamoto T, Yamamoto N, Ishikawa H, Nakano K, Unami N, Hamada K, Matsumura Y, Takamura F, Hattori K.
Abstract : The left-hand side (LHS) and central part of our first generation biphenyl (FGB) series was modified to improve in vitro and in vivo beta3-AR potency without loss of oral bioavailability. First, in this study, we focused our efforts on replacement of the 3-chlorophenyl moiety in the LHS of FGB analogues with 3-pyridyl ring analogues to adjust the lipophilicity. Second, we investigated the replacement of the central part of this series and discovered that introduction of a methyl group into the alpha-position of the phenethylamine moiety greatly enhanced potency keeping good oral availability. Finally, the replacement of the two carbon linker of the central part with an ethoxy-based linker provided improved potency and PK profiles. As a result of these studies, several analogues (i.e., 9h, 9k, 9l, 10g, 10m, 10p, 10r, 11b, and 11l) were identified that displayed an excellent balance of very higher human beta3-AR potency compared to the FGB compounds, high selectivity, and good pharmacokinetic profiles. Furthermore, these several compounds showed high in vivo efficacy in an overactive bladder (OAB) model. These findings suggest that our selected second generation biphenyl (SGB) series compounds may be attractive new successful therapeutic candidates for the treatment of OAB.
|
Agonist activity at human recombinant beta3 adrenergic receptor expressed in CHO cells assessed as cAMP accumulation by enzyme immuno assay
|
Homo sapiens
|
0.97
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of a novel series of biphenyl benzoic acid derivatives as highly potent and selective human beta3 adrenergic receptor agonists with good oral bioavailability. Part II.
Year : 2008
Volume : 51
Issue : 13
First Page : 4002
Last Page : 4020
Authors : Imanishi M, Itou S, Washizuka K, Hamashima H, Nakajima Y, Araki T, Tomishima Y, Sakurai M, Matsui S, Imamura E, Ueshima K, Yamamoto T, Yamamoto N, Ishikawa H, Nakano K, Unami N, Hamada K, Matsumura Y, Takamura F, Hattori K.
Abstract : The left-hand side (LHS) and central part of our first generation biphenyl (FGB) series was modified to improve in vitro and in vivo beta3-AR potency without loss of oral bioavailability. First, in this study, we focused our efforts on replacement of the 3-chlorophenyl moiety in the LHS of FGB analogues with 3-pyridyl ring analogues to adjust the lipophilicity. Second, we investigated the replacement of the central part of this series and discovered that introduction of a methyl group into the alpha-position of the phenethylamine moiety greatly enhanced potency keeping good oral availability. Finally, the replacement of the two carbon linker of the central part with an ethoxy-based linker provided improved potency and PK profiles. As a result of these studies, several analogues (i.e., 9h, 9k, 9l, 10g, 10m, 10p, 10r, 11b, and 11l) were identified that displayed an excellent balance of very higher human beta3-AR potency compared to the FGB compounds, high selectivity, and good pharmacokinetic profiles. Furthermore, these several compounds showed high in vivo efficacy in an overactive bladder (OAB) model. These findings suggest that our selected second generation biphenyl (SGB) series compounds may be attractive new successful therapeutic candidates for the treatment of OAB.
|
Agonist activity at human recombinant beta2 adrenergic receptor expressed in CHO cells assessed as cAMP accumulation by enzyme immuno assay
|
Homo sapiens
|
2.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of a novel series of biphenyl benzoic acid derivatives as highly potent and selective human beta3 adrenergic receptor agonists with good oral bioavailability. Part II.
Year : 2008
Volume : 51
Issue : 13
First Page : 4002
Last Page : 4020
Authors : Imanishi M, Itou S, Washizuka K, Hamashima H, Nakajima Y, Araki T, Tomishima Y, Sakurai M, Matsui S, Imamura E, Ueshima K, Yamamoto T, Yamamoto N, Ishikawa H, Nakano K, Unami N, Hamada K, Matsumura Y, Takamura F, Hattori K.
Abstract : The left-hand side (LHS) and central part of our first generation biphenyl (FGB) series was modified to improve in vitro and in vivo beta3-AR potency without loss of oral bioavailability. First, in this study, we focused our efforts on replacement of the 3-chlorophenyl moiety in the LHS of FGB analogues with 3-pyridyl ring analogues to adjust the lipophilicity. Second, we investigated the replacement of the central part of this series and discovered that introduction of a methyl group into the alpha-position of the phenethylamine moiety greatly enhanced potency keeping good oral availability. Finally, the replacement of the two carbon linker of the central part with an ethoxy-based linker provided improved potency and PK profiles. As a result of these studies, several analogues (i.e., 9h, 9k, 9l, 10g, 10m, 10p, 10r, 11b, and 11l) were identified that displayed an excellent balance of very higher human beta3-AR potency compared to the FGB compounds, high selectivity, and good pharmacokinetic profiles. Furthermore, these several compounds showed high in vivo efficacy in an overactive bladder (OAB) model. These findings suggest that our selected second generation biphenyl (SGB) series compounds may be attractive new successful therapeutic candidates for the treatment of OAB.
|
Agonist activity at human recombinant beta-1 adrenergic receptor expressed in CHO cells assessed as cAMP accumulation by enzyme immunoassay
|
Homo sapiens
|
0.84
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of highly potent and selective biphenylacylsulfonamide-based beta3-adrenergic receptor agonists and evaluation of physical properties as potential overactive bladder therapies: part 5.
Year : 2009
Volume : 52
Issue : 9
First Page : 3063
Last Page : 3072
Authors : Hattori K, Toda S, Imanishi M, Itou S, Nakajima Y, Washizuka K, Araki T, Hamashima H, Tomishima Y, Sakurai M, Matsui S, Imamura E, Ueshima K, Yamamoto T, Yamamoto N, Ishikawa H, Nakano K, Unami N, Hamada K, Matsumura Y, Takamura F.
Abstract : As an extension of research conducted on beta(3)-adrenergic receptor agonists as potential drugs for treating overactive bladder (OAB), novel series containing an acylsulfonamide moiety instead of the carboxylic acid moiety were evaluated. These compounds have been identified as potent and selective human beta(3)-AR agonists with improved oral bioavailability compared to the previous series. Results of structure-activity relationship (SAR) studies and cassette dosing evaluation in dogs showed several analogues (namely, 6h, 6j, 6o, 7e, and 9e) to have an excellent balance of in vitro potency and selectivity, pharmacokinetic (PK) profile, and an in vivo OAB model. Here we examined the relaxation response in dog detrusor muscle strips to a KCl induced tonic concentration. Results showed that the potency of in vitro relaxation response was not mirrored in the potency of the cAMP accumulation in CHO cell lines. Surprisingly, the EC(50) values of 6e and 7e found to induce relaxation of isolated bladder strips were over 50-fold higher than the cAMP accumulation in cell line. In general, increased lipophilicity led to decreased potency for the bladder relaxation compared with cAMP accumulation in CHO cell lines, indicating that lipophilicity is crucial for OAB drug candidates to improve beta(3) activity.
|
Agonist activity at human recombinant beta2 adrenergic receptor expressed in CHO cells assessed as cAMP accumulation by enzyme immunoassay
|
Homo sapiens
|
2.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of highly potent and selective biphenylacylsulfonamide-based beta3-adrenergic receptor agonists and evaluation of physical properties as potential overactive bladder therapies: part 5.
Year : 2009
Volume : 52
Issue : 9
First Page : 3063
Last Page : 3072
Authors : Hattori K, Toda S, Imanishi M, Itou S, Nakajima Y, Washizuka K, Araki T, Hamashima H, Tomishima Y, Sakurai M, Matsui S, Imamura E, Ueshima K, Yamamoto T, Yamamoto N, Ishikawa H, Nakano K, Unami N, Hamada K, Matsumura Y, Takamura F.
Abstract : As an extension of research conducted on beta(3)-adrenergic receptor agonists as potential drugs for treating overactive bladder (OAB), novel series containing an acylsulfonamide moiety instead of the carboxylic acid moiety were evaluated. These compounds have been identified as potent and selective human beta(3)-AR agonists with improved oral bioavailability compared to the previous series. Results of structure-activity relationship (SAR) studies and cassette dosing evaluation in dogs showed several analogues (namely, 6h, 6j, 6o, 7e, and 9e) to have an excellent balance of in vitro potency and selectivity, pharmacokinetic (PK) profile, and an in vivo OAB model. Here we examined the relaxation response in dog detrusor muscle strips to a KCl induced tonic concentration. Results showed that the potency of in vitro relaxation response was not mirrored in the potency of the cAMP accumulation in CHO cell lines. Surprisingly, the EC(50) values of 6e and 7e found to induce relaxation of isolated bladder strips were over 50-fold higher than the cAMP accumulation in cell line. In general, increased lipophilicity led to decreased potency for the bladder relaxation compared with cAMP accumulation in CHO cell lines, indicating that lipophilicity is crucial for OAB drug candidates to improve beta(3) activity.
|
Agonist activity at human recombinant beta3 adrenergic receptor expressed in CHO cells assessed as cAMP accumulation by enzyme immunoassay
|
Homo sapiens
|
0.97
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of highly potent and selective biphenylacylsulfonamide-based beta3-adrenergic receptor agonists and evaluation of physical properties as potential overactive bladder therapies: part 5.
Year : 2009
Volume : 52
Issue : 9
First Page : 3063
Last Page : 3072
Authors : Hattori K, Toda S, Imanishi M, Itou S, Nakajima Y, Washizuka K, Araki T, Hamashima H, Tomishima Y, Sakurai M, Matsui S, Imamura E, Ueshima K, Yamamoto T, Yamamoto N, Ishikawa H, Nakano K, Unami N, Hamada K, Matsumura Y, Takamura F.
Abstract : As an extension of research conducted on beta(3)-adrenergic receptor agonists as potential drugs for treating overactive bladder (OAB), novel series containing an acylsulfonamide moiety instead of the carboxylic acid moiety were evaluated. These compounds have been identified as potent and selective human beta(3)-AR agonists with improved oral bioavailability compared to the previous series. Results of structure-activity relationship (SAR) studies and cassette dosing evaluation in dogs showed several analogues (namely, 6h, 6j, 6o, 7e, and 9e) to have an excellent balance of in vitro potency and selectivity, pharmacokinetic (PK) profile, and an in vivo OAB model. Here we examined the relaxation response in dog detrusor muscle strips to a KCl induced tonic concentration. Results showed that the potency of in vitro relaxation response was not mirrored in the potency of the cAMP accumulation in CHO cell lines. Surprisingly, the EC(50) values of 6e and 7e found to induce relaxation of isolated bladder strips were over 50-fold higher than the cAMP accumulation in cell line. In general, increased lipophilicity led to decreased potency for the bladder relaxation compared with cAMP accumulation in CHO cell lines, indicating that lipophilicity is crucial for OAB drug candidates to improve beta(3) activity.
|
Agonist activity at human beta-1 adrenergic receptor expressed in CHO cells assessed as cAMP accumulation
|
Homo sapiens
|
100.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and evaluation of novel phenoxypropanolamine derivatives containing acetanilides as potent and selective beta3-adrenergic receptor agonists.
Year : 2009
Volume : 17
Issue : 9
First Page : 3283
Last Page : 3294
Authors : Maruyama T, Onda K, Hayakawa M, Seki N, Takahashi T, Moritomo H, Suzuki T, Matsui T, Takasu T, Nagase I, Ohta M.
Abstract : In the search for potent and selective human beta3-adrenergic receptor (AR) agonists as potential drugs for the treatment of obesity and noninsulin-dependent (type II) diabetes, a novel series of phenoxypropanolamine derivatives containing acetanilides were prepared and their biological activities were evaluated at the human beta3-, beta2-, and beta1-ARs. Several of the analogues (21a, 21b, and 27a) exhibited potent agonistic activity at the beta3-AR. Among the compounds described herein, the N-methyl-1-benzylimidazol-2-ylacetanilide derivative (21b) was found to be the most potent and selective beta3-AR agonist, with an EC(50) value of 0.28 microM and no agonistic activity for either the beta1- or beta2-AR. In addition, 21b showed significant hypoglycemic activity in a rodent diabetic model.
|
Agonist activity at human beta2 adrenergic receptor expressed in CHO cells assessed as cAMP accumulation
|
Homo sapiens
|
3.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and evaluation of novel phenoxypropanolamine derivatives containing acetanilides as potent and selective beta3-adrenergic receptor agonists.
Year : 2009
Volume : 17
Issue : 9
First Page : 3283
Last Page : 3294
Authors : Maruyama T, Onda K, Hayakawa M, Seki N, Takahashi T, Moritomo H, Suzuki T, Matsui T, Takasu T, Nagase I, Ohta M.
Abstract : In the search for potent and selective human beta3-adrenergic receptor (AR) agonists as potential drugs for the treatment of obesity and noninsulin-dependent (type II) diabetes, a novel series of phenoxypropanolamine derivatives containing acetanilides were prepared and their biological activities were evaluated at the human beta3-, beta2-, and beta1-ARs. Several of the analogues (21a, 21b, and 27a) exhibited potent agonistic activity at the beta3-AR. Among the compounds described herein, the N-methyl-1-benzylimidazol-2-ylacetanilide derivative (21b) was found to be the most potent and selective beta3-AR agonist, with an EC(50) value of 0.28 microM and no agonistic activity for either the beta1- or beta2-AR. In addition, 21b showed significant hypoglycemic activity in a rodent diabetic model.
|
Agonist activity at human beta3 adrenergic receptor expressed in CHO cells assessed as cAMP accumulation
|
Homo sapiens
|
12.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and evaluation of novel phenoxypropanolamine derivatives containing acetanilides as potent and selective beta3-adrenergic receptor agonists.
Year : 2009
Volume : 17
Issue : 9
First Page : 3283
Last Page : 3294
Authors : Maruyama T, Onda K, Hayakawa M, Seki N, Takahashi T, Moritomo H, Suzuki T, Matsui T, Takasu T, Nagase I, Ohta M.
Abstract : In the search for potent and selective human beta3-adrenergic receptor (AR) agonists as potential drugs for the treatment of obesity and noninsulin-dependent (type II) diabetes, a novel series of phenoxypropanolamine derivatives containing acetanilides were prepared and their biological activities were evaluated at the human beta3-, beta2-, and beta1-ARs. Several of the analogues (21a, 21b, and 27a) exhibited potent agonistic activity at the beta3-AR. Among the compounds described herein, the N-methyl-1-benzylimidazol-2-ylacetanilide derivative (21b) was found to be the most potent and selective beta3-AR agonist, with an EC(50) value of 0.28 microM and no agonistic activity for either the beta1- or beta2-AR. In addition, 21b showed significant hypoglycemic activity in a rodent diabetic model.
|
Agonist activity at human cloned beta3 adrenergic receptor expressed in CHO cells assessed as cAMP accumulation
|
Homo sapiens
|
0.97
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of a novel series of benzoic acid derivatives as potent and selective human beta3 adrenergic receptor agonists with good oral bioavailability. 3. Phenylethanolaminotetraline (PEAT) skeleton containing biphenyl or biphenyl ether moiety.
Year : 2008
Volume : 51
Issue : 15
First Page : 4804
Last Page : 4822
Authors : Imanishi M, Nakajima Y, Tomishima Y, Hamashima H, Washizuka K, Sakurai M, Matsui S, Imamura E, Ueshima K, Yamamoto T, Yamamoto N, Ishikawa H, Nakano K, Unami N, Hamada K, Matsumura Y, Takamura F, Hattori K.
Abstract : We designed a series of benzoic acid derivatives containing the biphenyl ether or biphenyl template on the RHS and a phenylethanolaminotetraline (PEAT) skeleton, which was prepared by highly stereoselective synthesis, to generate two structurally different lead compounds ( 10c, 10m) with a good balance of potency, selectivity, and pharmacokinetic profile. Further optimization of the two lead compounds to improve potency led to several potential candidates (i.e., 11f, 11l, 11o, 12b). In particular, biphenyl analogue 12b exhibited an excellent balance of high potency (EC50 = 0.38 nM) for beta3, high selectivity over beta1 and beta2, and good pharmacokinetic properties in rats, dogs, and monkeys.
|
Agonist activity at human cloned beta-1 adrenergic receptor expressed in CHO cells assessed as cAMP accumulation
|
Homo sapiens
|
0.084
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of a novel series of benzoic acid derivatives as potent and selective human beta3 adrenergic receptor agonists with good oral bioavailability. 3. Phenylethanolaminotetraline (PEAT) skeleton containing biphenyl or biphenyl ether moiety.
Year : 2008
Volume : 51
Issue : 15
First Page : 4804
Last Page : 4822
Authors : Imanishi M, Nakajima Y, Tomishima Y, Hamashima H, Washizuka K, Sakurai M, Matsui S, Imamura E, Ueshima K, Yamamoto T, Yamamoto N, Ishikawa H, Nakano K, Unami N, Hamada K, Matsumura Y, Takamura F, Hattori K.
Abstract : We designed a series of benzoic acid derivatives containing the biphenyl ether or biphenyl template on the RHS and a phenylethanolaminotetraline (PEAT) skeleton, which was prepared by highly stereoselective synthesis, to generate two structurally different lead compounds ( 10c, 10m) with a good balance of potency, selectivity, and pharmacokinetic profile. Further optimization of the two lead compounds to improve potency led to several potential candidates (i.e., 11f, 11l, 11o, 12b). In particular, biphenyl analogue 12b exhibited an excellent balance of high potency (EC50 = 0.38 nM) for beta3, high selectivity over beta1 and beta2, and good pharmacokinetic properties in rats, dogs, and monkeys.
|
Agonist activity at human beta2 adrenergic receptor expressed in CHO cells assessed as cAMP accumulation
|
Homo sapiens
|
2.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of a novel series of benzoic acid derivatives as potent and selective human beta3 adrenergic receptor agonists with good oral bioavailability. 3. Phenylethanolaminotetraline (PEAT) skeleton containing biphenyl or biphenyl ether moiety.
Year : 2008
Volume : 51
Issue : 15
First Page : 4804
Last Page : 4822
Authors : Imanishi M, Nakajima Y, Tomishima Y, Hamashima H, Washizuka K, Sakurai M, Matsui S, Imamura E, Ueshima K, Yamamoto T, Yamamoto N, Ishikawa H, Nakano K, Unami N, Hamada K, Matsumura Y, Takamura F, Hattori K.
Abstract : We designed a series of benzoic acid derivatives containing the biphenyl ether or biphenyl template on the RHS and a phenylethanolaminotetraline (PEAT) skeleton, which was prepared by highly stereoselective synthesis, to generate two structurally different lead compounds ( 10c, 10m) with a good balance of potency, selectivity, and pharmacokinetic profile. Further optimization of the two lead compounds to improve potency led to several potential candidates (i.e., 11f, 11l, 11o, 12b). In particular, biphenyl analogue 12b exhibited an excellent balance of high potency (EC50 = 0.38 nM) for beta3, high selectivity over beta1 and beta2, and good pharmacokinetic properties in rats, dogs, and monkeys.
|
Agonist activity at human cloned adrenergic beta3 receptor expressed in CHO cells assessed as cAMP accumulation
|
Homo sapiens
|
0.97
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of novel series of benzoic acid derivatives containing biphenyl ether moiety as potent and selective human beta(3)-adrenergic receptor agonists: Part IV.
Year : 2008
Volume : 18
Issue : 18
First Page : 5037
Last Page : 5040
Authors : Nakajima Y, Imanishi M, Itou S, Hamashima H, Tomishima Y, Washizuka K, Sakurai M, Matsui S, Imamura E, Ueshima K, Yamamoto T, Yamamoto N, Ishikawa H, Nakano K, Unami N, Hamada K, Hattori K.
Abstract : Identification and SAR study of novel series of beta(3)-AR agonists with benzoic acid are described. Conversion of ether linkage position of phenoxybenzoic acid derivative 2b led to compound 7b with moderate beta(3)-AR activity. Further modification in right, center and left parts of compound 7b was investigated to improve the beta(3)-AR potency and selectivity. Compounds 7g and 7k, with the bulky aliphatic-substituted group at 2-position of benzoic acid moiety, were identified as potent and selective beta(3)-AR agonists. In addition, in vivo efficacy of compounds 7g and 7k was exhibited on dog OAB model.
|
Agonist activity at human cloned adrenergic beta-1 receptor expressed in CHO cells assessed as cAMP accumulation
|
Homo sapiens
|
0.084
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of novel series of benzoic acid derivatives containing biphenyl ether moiety as potent and selective human beta(3)-adrenergic receptor agonists: Part IV.
Year : 2008
Volume : 18
Issue : 18
First Page : 5037
Last Page : 5040
Authors : Nakajima Y, Imanishi M, Itou S, Hamashima H, Tomishima Y, Washizuka K, Sakurai M, Matsui S, Imamura E, Ueshima K, Yamamoto T, Yamamoto N, Ishikawa H, Nakano K, Unami N, Hamada K, Hattori K.
Abstract : Identification and SAR study of novel series of beta(3)-AR agonists with benzoic acid are described. Conversion of ether linkage position of phenoxybenzoic acid derivative 2b led to compound 7b with moderate beta(3)-AR activity. Further modification in right, center and left parts of compound 7b was investigated to improve the beta(3)-AR potency and selectivity. Compounds 7g and 7k, with the bulky aliphatic-substituted group at 2-position of benzoic acid moiety, were identified as potent and selective beta(3)-AR agonists. In addition, in vivo efficacy of compounds 7g and 7k was exhibited on dog OAB model.
|
Agonist activity at human cloned beta-1 adrenergic receptor expressed in CHO cells assessed as induction of intracellular cAMP accumulation by beta-galactosidase based whole cell assay
|
Homo sapiens
|
7.943
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of long-acting beta2 adrenergic receptor agonists incorporating arylsulfonamide groups.
Year : 2009
Volume : 52
Issue : 8
First Page : 2280
Last Page : 2288
Authors : Procopiou PA, Barrett VJ, Bevan NJ, Biggadike K, Butchers PR, Coe DM, Conroy R, Edney DD, Field RN, Ford AJ, Guntrip SB, Looker BE, McLay IM, Monteith MJ, Morrison VS, Mutch PJ, Richards SA, Sasse R, Smith CE.
Abstract : A series of saligenin alkoxyalkylphenylsulfonamide beta(2) adrenoceptor agonists were prepared by reacting a protected saligenin oxazolidinone with alkynyloxyalkyl bromides, followed by Sonogashira reaction, hydrogenation, and deprotection. The meta-substituted primary sulfonamide was more potent than the para- and the ortho-analogues. Primary sulfonamides were more potent than the secondary and tertiary analogues. The onset and duration of action in vitro of selected compounds was assessed on isolated superfused guinea pig trachea. Sulfonamide 29b had the best profile of potency, selectivity, onset, and duration of action on both guinea pig trachea and human bronchus. Furthermore, 29b was found to have low oral bioavailability in rat and dog and also to have long duration of action in an in vivo model of bronchodilation. Crystalline salts of 29b were identified that had suitable properties for inhaled administration. A proposed binding mode for 29b to the beta(2)-receptor is presented.
|
Agonist activity at human cloned beta2 adrenergic receptor expressed in CHO cells assessed as induction of intracellular cAMP accumulation by beta-galactosidase based whole cell assay
|
Homo sapiens
|
39.81
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of long-acting beta2 adrenergic receptor agonists incorporating arylsulfonamide groups.
Year : 2009
Volume : 52
Issue : 8
First Page : 2280
Last Page : 2288
Authors : Procopiou PA, Barrett VJ, Bevan NJ, Biggadike K, Butchers PR, Coe DM, Conroy R, Edney DD, Field RN, Ford AJ, Guntrip SB, Looker BE, McLay IM, Monteith MJ, Morrison VS, Mutch PJ, Richards SA, Sasse R, Smith CE.
Abstract : A series of saligenin alkoxyalkylphenylsulfonamide beta(2) adrenoceptor agonists were prepared by reacting a protected saligenin oxazolidinone with alkynyloxyalkyl bromides, followed by Sonogashira reaction, hydrogenation, and deprotection. The meta-substituted primary sulfonamide was more potent than the para- and the ortho-analogues. Primary sulfonamides were more potent than the secondary and tertiary analogues. The onset and duration of action in vitro of selected compounds was assessed on isolated superfused guinea pig trachea. Sulfonamide 29b had the best profile of potency, selectivity, onset, and duration of action on both guinea pig trachea and human bronchus. Furthermore, 29b was found to have low oral bioavailability in rat and dog and also to have long duration of action in an in vivo model of bronchodilation. Crystalline salts of 29b were identified that had suitable properties for inhaled administration. A proposed binding mode for 29b to the beta(2)-receptor is presented.
|
Agonist activity at human cloned beta3 adrenergic receptor expressed in CHO cells assessed as induction of intracellular cAMP accumulation by beta-galactosidase based whole cell assay
|
Homo sapiens
|
39.81
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of long-acting beta2 adrenergic receptor agonists incorporating arylsulfonamide groups.
Year : 2009
Volume : 52
Issue : 8
First Page : 2280
Last Page : 2288
Authors : Procopiou PA, Barrett VJ, Bevan NJ, Biggadike K, Butchers PR, Coe DM, Conroy R, Edney DD, Field RN, Ford AJ, Guntrip SB, Looker BE, McLay IM, Monteith MJ, Morrison VS, Mutch PJ, Richards SA, Sasse R, Smith CE.
Abstract : A series of saligenin alkoxyalkylphenylsulfonamide beta(2) adrenoceptor agonists were prepared by reacting a protected saligenin oxazolidinone with alkynyloxyalkyl bromides, followed by Sonogashira reaction, hydrogenation, and deprotection. The meta-substituted primary sulfonamide was more potent than the para- and the ortho-analogues. Primary sulfonamides were more potent than the secondary and tertiary analogues. The onset and duration of action in vitro of selected compounds was assessed on isolated superfused guinea pig trachea. Sulfonamide 29b had the best profile of potency, selectivity, onset, and duration of action on both guinea pig trachea and human bronchus. Furthermore, 29b was found to have low oral bioavailability in rat and dog and also to have long duration of action in an in vivo model of bronchodilation. Crystalline salts of 29b were identified that had suitable properties for inhaled administration. A proposed binding mode for 29b to the beta(2)-receptor is presented.
|
Agonist activity at human cloned adrenergic beta3 receptor expressed in CHO cells assessed as increase in cAMP production after 2 days by radioimmunoassay
|
Homo sapiens
|
100.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Discovery of novel acetanilide derivatives as potent and selective beta3-adrenergic receptor agonists.
Year : 2009
Volume : 44
Issue : 6
First Page : 2533
Last Page : 2543
Authors : Maruyama T, Onda K, Hayakawa M, Matsui T, Takasu T, Ohta M.
Abstract : In the search for potent and selective human beta3-adrenergic receptor (AR) agonists as potential drugs for the treatment of obesity and noninsulin-dependent (type II) diabetes, a novel series of acetanilide-based analogues were prepared and their biological activities were evaluated at the human beta3-, beta2-, and beta1-ARs. Among these compounds, 2-pyridylacetanilide (2f), pyrimidin-2-ylacetanilide (2u), and pyrazin-2-ylacetanilide (2v) derivatives exhibited potent agonistic activity at the beta3-AR with functional selectivity over the beta1- and beta2-ARs. In particular, compound 2u was found to be the most potent and selective beta3-AR agonist with an EC(50) value of 0.11 microM and no agonistic activity for either the beta1- or beta2-AR. In addition, 2f, 2u, and 2v showed significant hypoglycemic activity in a rodent diabetic model.
|
Agonist activity at human cloned adrenergic beta2 receptor expressed in CHO cells assessed as increase in cAMP production after 2 days by radioimmunoassay
|
Homo sapiens
|
3.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Discovery of novel acetanilide derivatives as potent and selective beta3-adrenergic receptor agonists.
Year : 2009
Volume : 44
Issue : 6
First Page : 2533
Last Page : 2543
Authors : Maruyama T, Onda K, Hayakawa M, Matsui T, Takasu T, Ohta M.
Abstract : In the search for potent and selective human beta3-adrenergic receptor (AR) agonists as potential drugs for the treatment of obesity and noninsulin-dependent (type II) diabetes, a novel series of acetanilide-based analogues were prepared and their biological activities were evaluated at the human beta3-, beta2-, and beta1-ARs. Among these compounds, 2-pyridylacetanilide (2f), pyrimidin-2-ylacetanilide (2u), and pyrazin-2-ylacetanilide (2v) derivatives exhibited potent agonistic activity at the beta3-AR with functional selectivity over the beta1- and beta2-ARs. In particular, compound 2u was found to be the most potent and selective beta3-AR agonist with an EC(50) value of 0.11 microM and no agonistic activity for either the beta1- or beta2-AR. In addition, 2f, 2u, and 2v showed significant hypoglycemic activity in a rodent diabetic model.
|
Agonist activity at human cloned adrenergic beta-1 receptor expressed in CHO cells assessed as increase in cAMP production after 2 days by radioimmunoassay
|
Homo sapiens
|
12.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Discovery of novel acetanilide derivatives as potent and selective beta3-adrenergic receptor agonists.
Year : 2009
Volume : 44
Issue : 6
First Page : 2533
Last Page : 2543
Authors : Maruyama T, Onda K, Hayakawa M, Matsui T, Takasu T, Ohta M.
Abstract : In the search for potent and selective human beta3-adrenergic receptor (AR) agonists as potential drugs for the treatment of obesity and noninsulin-dependent (type II) diabetes, a novel series of acetanilide-based analogues were prepared and their biological activities were evaluated at the human beta3-, beta2-, and beta1-ARs. Among these compounds, 2-pyridylacetanilide (2f), pyrimidin-2-ylacetanilide (2u), and pyrazin-2-ylacetanilide (2v) derivatives exhibited potent agonistic activity at the beta3-AR with functional selectivity over the beta1- and beta2-ARs. In particular, compound 2u was found to be the most potent and selective beta3-AR agonist with an EC(50) value of 0.11 microM and no agonistic activity for either the beta1- or beta2-AR. In addition, 2f, 2u, and 2v showed significant hypoglycemic activity in a rodent diabetic model.
|
Binding affinity to human adrenergic beta2 receptor
|
Homo sapiens
|
50.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis, pharmacological and in silico evaluation of 1-(4-di-hydroxy-3,5-dioxa-4-borabicyclo[4.4.0]deca-7,9,11-trien-9-yl)-2-(tert-butylamino)ethanol, a compound designed to act as a beta2 adrenoceptor agonist.
Year : 2009
Volume : 44
Issue : 7
First Page : 2840
Last Page : 2846
Authors : Soriano-Ursúa MA, Valencia-Hernández I, Arellano-Mendoza MG, Correa-Basurto J, Trujillo-Ferrara JG.
Abstract : In this study, 1-(4-di-hydroxy-3,5-dioxa-4-borabicyclo[4.4.0]deca-7,9,11-trien-9-yl)-2-(tert-butylamino)ethanol, (BR-AEA), was designed, synthesized, characterized and tested in docking studies and in vitro. Previous to its synthesis, a set of compounds, including well-known ligands and boron containing compounds, were studied under docking simulations. BR-AEA showed greater affinity than these well-known agonists and was found to be slightly closer than salbutamol to the residues in the TM5 and TM3 of the beta(2) adrenoceptor (beta(2)AR), making a greater number of interactions with them, including some that are apparently key to greater affinity and beta(2)AR activation. This study suggests that affinity is closely related to the interactions of the boron atom, as well as the capacity of boronic acid moieties to make a network of hydrogen bonds with the beta(2)AR. In vitro, the relaxing effects of BR-AEA on isolated guinea pig tracheal rings were compared with salbutamol. The EC(50) values for BR-AEA were at least five-fold lower than for salbutamol, showing the greater potency of the former. Additionally, propranolol and ICI 118,551 showed competitive antagonism in relation to the relaxing effect of the test compound (pA(2) 6.204+/-0.367 and 9.089+/-0.470, respectively).
|
Agonist activity at human cloned adrenergic beta3 receptor expressed in CHO cells assessed as [125I]cAMP accumulation after 2 days by radioimmunoassay
|
Homo sapiens
|
100.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery of novel thiourea derivatives as potent and selective beta3-adrenergic receptor agonists.
Year : 2009
Volume : 17
Issue : 15
First Page : 5510
Last Page : 5519
Authors : Maruyama T, Seki N, Onda K, Suzuki T, Kawazoe S, Hayakawa M, Matsui T, Takasu T, Ohta M.
Abstract : In the search for potent and selective human beta3-adrenergic receptor (AR) agonists as potential drugs for the treatment of obesity and noninsulin-dependent (type II) diabetes, we prepared a novel series of phenoxypropanolamine derivatives containing the thiourea moiety and evaluated their biological activities at human beta3-, beta2-, and beta1-ARs. Among these compounds, 4-nitrophenylthiourea (18i) and 3-methoxyphenylthiourea (18k) derivatives were found to exhibit potent agonistic activity at the beta3-AR, with EC(50) values of 0.10 and 0.16 microM, respectively, and no agonistic activity for either the beta1- or beta2-AR. In addition, they showed significant hypoglycemic activity in a rodent diabetic model.
|
Agonist activity at human cloned adrenergic beta2 receptor expressed in CHO cells assessed as [125I]cAMP accumulation after 2 days by radioimmunoassay
|
Homo sapiens
|
3.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery of novel thiourea derivatives as potent and selective beta3-adrenergic receptor agonists.
Year : 2009
Volume : 17
Issue : 15
First Page : 5510
Last Page : 5519
Authors : Maruyama T, Seki N, Onda K, Suzuki T, Kawazoe S, Hayakawa M, Matsui T, Takasu T, Ohta M.
Abstract : In the search for potent and selective human beta3-adrenergic receptor (AR) agonists as potential drugs for the treatment of obesity and noninsulin-dependent (type II) diabetes, we prepared a novel series of phenoxypropanolamine derivatives containing the thiourea moiety and evaluated their biological activities at human beta3-, beta2-, and beta1-ARs. Among these compounds, 4-nitrophenylthiourea (18i) and 3-methoxyphenylthiourea (18k) derivatives were found to exhibit potent agonistic activity at the beta3-AR, with EC(50) values of 0.10 and 0.16 microM, respectively, and no agonistic activity for either the beta1- or beta2-AR. In addition, they showed significant hypoglycemic activity in a rodent diabetic model.
|
Agonist activity at human cloned adrenergic beta-1 receptor expressed in CHO cells assessed as [125I]cAMP accumulation after 2 days by radioimmunoassay
|
Homo sapiens
|
12.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery of novel thiourea derivatives as potent and selective beta3-adrenergic receptor agonists.
Year : 2009
Volume : 17
Issue : 15
First Page : 5510
Last Page : 5519
Authors : Maruyama T, Seki N, Onda K, Suzuki T, Kawazoe S, Hayakawa M, Matsui T, Takasu T, Ohta M.
Abstract : In the search for potent and selective human beta3-adrenergic receptor (AR) agonists as potential drugs for the treatment of obesity and noninsulin-dependent (type II) diabetes, we prepared a novel series of phenoxypropanolamine derivatives containing the thiourea moiety and evaluated their biological activities at human beta3-, beta2-, and beta1-ARs. Among these compounds, 4-nitrophenylthiourea (18i) and 3-methoxyphenylthiourea (18k) derivatives were found to exhibit potent agonistic activity at the beta3-AR, with EC(50) values of 0.10 and 0.16 microM, respectively, and no agonistic activity for either the beta1- or beta2-AR. In addition, they showed significant hypoglycemic activity in a rodent diabetic model.
|
Agonist activity at human recombinant adrenergic beta3 receptor expressed in CHO cells assessed as stimulation of cAMP level after 1 hr by enzyme immunoassay
|
Homo sapiens
|
2.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of highly potent and selective biphenylacylsulfonamide-based beta3-adrenergic receptor agonists and molecular modeling based on the solved X-ray structure of the beta2-adrenergic receptor: part 6.
Year : 2009
Volume : 19
Issue : 16
First Page : 4679
Last Page : 4683
Authors : Hattori K, Orita M, Toda S, Imanishi M, Itou S, Nakajima Y, Tanabe D, Washizuka K, Araki T, Sakurai M, Matsui S, Imamura E, Ueshima K, Yamamoto T, Yamamoto N, Ishikawa H, Nakano K, Unami N, Hamada K, Matsumura Y, Takamura F.
Abstract : As an extension of research, we have investigated modification of left-hand side (LHS) of biphenyl analogues containing an acylsulfonamide moiety in the development of potent and selective human beta(3)-adrenergic receptor (AR) agonists. Result of structure-activity relationships (SAR) and cassette-dosing evaluation in dogs showed that the hydroxynorephedrine analogue 16 had an excellent balance of in vitro and in vivo potency with pharmacokinetic profiles. In addition, to facilitate structure-based drug design (SBDD), we also have performed a docking study of biphenyl analogues based on the X-ray structure of the beta(2)-adrenergic receptor.
|
Agonist activity at human recombinant adrenergic beta2 receptor expressed in CHO cells assessed as stimulation of cAMP level after 1 hr by enzyme immunoassay
|
Homo sapiens
|
0.84
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of highly potent and selective biphenylacylsulfonamide-based beta3-adrenergic receptor agonists and molecular modeling based on the solved X-ray structure of the beta2-adrenergic receptor: part 6.
Year : 2009
Volume : 19
Issue : 16
First Page : 4679
Last Page : 4683
Authors : Hattori K, Orita M, Toda S, Imanishi M, Itou S, Nakajima Y, Tanabe D, Washizuka K, Araki T, Sakurai M, Matsui S, Imamura E, Ueshima K, Yamamoto T, Yamamoto N, Ishikawa H, Nakano K, Unami N, Hamada K, Matsumura Y, Takamura F.
Abstract : As an extension of research, we have investigated modification of left-hand side (LHS) of biphenyl analogues containing an acylsulfonamide moiety in the development of potent and selective human beta(3)-adrenergic receptor (AR) agonists. Result of structure-activity relationships (SAR) and cassette-dosing evaluation in dogs showed that the hydroxynorephedrine analogue 16 had an excellent balance of in vitro and in vivo potency with pharmacokinetic profiles. In addition, to facilitate structure-based drug design (SBDD), we also have performed a docking study of biphenyl analogues based on the X-ray structure of the beta(2)-adrenergic receptor.
|
Agonist activity at human recombinant beta2 adrenergic receptor expressed in CHO cells assessed as induction of intracellular cAMP accumulation after 30 to 45 mins
|
Homo sapiens
|
39.81
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of long-acting beta2 adrenergic receptor agonists incorporating metabolic inactivation: an antedrug approach.
Year : 2010
Volume : 53
Issue : 11
First Page : 4522
Last Page : 4530
Authors : Procopiou PA, Barrett VJ, Bevan NJ, Biggadike K, Box PC, Butchers PR, Coe DM, Conroy R, Emmons A, Ford AJ, Holmes DS, Horsley H, Kerr F, Li-Kwai-Cheung AM, Looker BE, Mann IS, McLay IM, Morrison VS, Mutch PJ, Smith CE, Tomlin P.
Abstract : A series of saligenin beta(2) adrenoceptor agonist antedrugs having high clearance were prepared by reacting a protected saligenin oxazolidinone with protected hydroxyethoxyalkoxyalkyl bromides, followed by removal of the hydroxy-protecting group, alkylation, and final deprotection. The compounds were screened for beta(2), beta(1), and beta(3) agonist activity in CHO cells. The onset and duration of action in vitro of selected compounds were assessed on isolated superfused guinea pig trachea. Compound 13f had high potency, selectivity, fast onset, and long duration of action in vitro and was found to have long duration in vivo, low oral bioavailability in the rat, and to be rapidly metabolized. Crystalline salts of 13f (vilanterol) were identified that had suitable properties for inhaled administration. A proposed binding mode for 13f to the beta(2)-receptor is presented.
|
Agonist activity at human recombinant beta-1 adrenergic receptor expressed in CHO cells assessed as induction of intracellular cAMP accumulation after 30 to 45 mins
|
Homo sapiens
|
7.943
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of long-acting beta2 adrenergic receptor agonists incorporating metabolic inactivation: an antedrug approach.
Year : 2010
Volume : 53
Issue : 11
First Page : 4522
Last Page : 4530
Authors : Procopiou PA, Barrett VJ, Bevan NJ, Biggadike K, Box PC, Butchers PR, Coe DM, Conroy R, Emmons A, Ford AJ, Holmes DS, Horsley H, Kerr F, Li-Kwai-Cheung AM, Looker BE, Mann IS, McLay IM, Morrison VS, Mutch PJ, Smith CE, Tomlin P.
Abstract : A series of saligenin beta(2) adrenoceptor agonist antedrugs having high clearance were prepared by reacting a protected saligenin oxazolidinone with protected hydroxyethoxyalkoxyalkyl bromides, followed by removal of the hydroxy-protecting group, alkylation, and final deprotection. The compounds were screened for beta(2), beta(1), and beta(3) agonist activity in CHO cells. The onset and duration of action in vitro of selected compounds were assessed on isolated superfused guinea pig trachea. Compound 13f had high potency, selectivity, fast onset, and long duration of action in vitro and was found to have long duration in vivo, low oral bioavailability in the rat, and to be rapidly metabolized. Crystalline salts of 13f (vilanterol) were identified that had suitable properties for inhaled administration. A proposed binding mode for 13f to the beta(2)-receptor is presented.
|
Agonist activity at human recombinant beta3 adrenergic receptor expressed in CHO cells assessed as induction of intracellular cAMP accumulation after 30 to 45 mins
|
Homo sapiens
|
39.81
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and structure-activity relationships of long-acting beta2 adrenergic receptor agonists incorporating metabolic inactivation: an antedrug approach.
Year : 2010
Volume : 53
Issue : 11
First Page : 4522
Last Page : 4530
Authors : Procopiou PA, Barrett VJ, Bevan NJ, Biggadike K, Box PC, Butchers PR, Coe DM, Conroy R, Emmons A, Ford AJ, Holmes DS, Horsley H, Kerr F, Li-Kwai-Cheung AM, Looker BE, Mann IS, McLay IM, Morrison VS, Mutch PJ, Smith CE, Tomlin P.
Abstract : A series of saligenin beta(2) adrenoceptor agonist antedrugs having high clearance were prepared by reacting a protected saligenin oxazolidinone with protected hydroxyethoxyalkoxyalkyl bromides, followed by removal of the hydroxy-protecting group, alkylation, and final deprotection. The compounds were screened for beta(2), beta(1), and beta(3) agonist activity in CHO cells. The onset and duration of action in vitro of selected compounds were assessed on isolated superfused guinea pig trachea. Compound 13f had high potency, selectivity, fast onset, and long duration of action in vitro and was found to have long duration in vivo, low oral bioavailability in the rat, and to be rapidly metabolized. Crystalline salts of 13f (vilanterol) were identified that had suitable properties for inhaled administration. A proposed binding mode for 13f to the beta(2)-receptor is presented.
|
Binding affinity to human beta-2 adrenergic receptor delta 5-C271 mutant expressed in Spodoptera frugiperda Sf9 cells
|
Homo sapiens
|
90.0
nM
|
|
Journal : Nat. Chem. Biol.
Title : Coupling ligand structure to specific conformational switches in the beta2-adrenoceptor.
Year : 2006
Volume : 2
Issue : 8
First Page : 417
Last Page : 422
Authors : Yao X, Parnot C, Deupi X, Ratnala VR, Swaminath G, Farrens D, Kobilka B.
Abstract : G protein-coupled receptors (GPCRs) regulate a wide variety of physiological functions in response to structurally diverse ligands ranging from cations and small organic molecules to peptides and glycoproteins. For many GPCRs, structurally related ligands can have diverse efficacy profiles. To investigate the process of ligand binding and activation, we used fluorescence spectroscopy to study the ability of ligands having different efficacies to induce a specific conformational change in the human beta2-adrenoceptor (beta2-AR). The 'ionic lock' is a molecular switch found in rhodopsin-family GPCRs that has been proposed to link the cytoplasmic ends of transmembrane domains 3 and 6 in the inactive state. We found that most partial agonists were as effective as full agonists in disrupting the ionic lock. Our results show that disruption of this important molecular switch is necessary, but not sufficient, for full activation of the beta2-AR.
|
Displacement of [3H]dihydroalprenolol from human beta-2 adrenergic receptor delta 5-C271/W135 mutant labeled with bimane by competition binding assay
|
Homo sapiens
|
150.0
nM
|
|
Journal : Nat. Chem. Biol.
Title : Coupling ligand structure to specific conformational switches in the beta2-adrenoceptor.
Year : 2006
Volume : 2
Issue : 8
First Page : 417
Last Page : 422
Authors : Yao X, Parnot C, Deupi X, Ratnala VR, Swaminath G, Farrens D, Kobilka B.
Abstract : G protein-coupled receptors (GPCRs) regulate a wide variety of physiological functions in response to structurally diverse ligands ranging from cations and small organic molecules to peptides and glycoproteins. For many GPCRs, structurally related ligands can have diverse efficacy profiles. To investigate the process of ligand binding and activation, we used fluorescence spectroscopy to study the ability of ligands having different efficacies to induce a specific conformational change in the human beta2-adrenoceptor (beta2-AR). The 'ionic lock' is a molecular switch found in rhodopsin-family GPCRs that has been proposed to link the cytoplasmic ends of transmembrane domains 3 and 6 in the inactive state. We found that most partial agonists were as effective as full agonists in disrupting the ionic lock. Our results show that disruption of this important molecular switch is necessary, but not sufficient, for full activation of the beta2-AR.
|
Displacement of [3H]dihydroalprenolol from human beta-2 adrenergic receptor delta 5-C271/W135 mutant by competition binding assay
|
Homo sapiens
|
370.0
nM
|
|
Journal : Nat. Chem. Biol.
Title : Coupling ligand structure to specific conformational switches in the beta2-adrenoceptor.
Year : 2006
Volume : 2
Issue : 8
First Page : 417
Last Page : 422
Authors : Yao X, Parnot C, Deupi X, Ratnala VR, Swaminath G, Farrens D, Kobilka B.
Abstract : G protein-coupled receptors (GPCRs) regulate a wide variety of physiological functions in response to structurally diverse ligands ranging from cations and small organic molecules to peptides and glycoproteins. For many GPCRs, structurally related ligands can have diverse efficacy profiles. To investigate the process of ligand binding and activation, we used fluorescence spectroscopy to study the ability of ligands having different efficacies to induce a specific conformational change in the human beta2-adrenoceptor (beta2-AR). The 'ionic lock' is a molecular switch found in rhodopsin-family GPCRs that has been proposed to link the cytoplasmic ends of transmembrane domains 3 and 6 in the inactive state. We found that most partial agonists were as effective as full agonists in disrupting the ionic lock. Our results show that disruption of this important molecular switch is necessary, but not sufficient, for full activation of the beta2-AR.
|
Binding affinity to human beta-2 adrenergic receptor delta 5-C271/W135 mutant expressed in Spodoptera frugiperda Sf9 cells
|
Homo sapiens
|
50.0
nM
|
|
Journal : Nat. Chem. Biol.
Title : Coupling ligand structure to specific conformational switches in the beta2-adrenoceptor.
Year : 2006
Volume : 2
Issue : 8
First Page : 417
Last Page : 422
Authors : Yao X, Parnot C, Deupi X, Ratnala VR, Swaminath G, Farrens D, Kobilka B.
Abstract : G protein-coupled receptors (GPCRs) regulate a wide variety of physiological functions in response to structurally diverse ligands ranging from cations and small organic molecules to peptides and glycoproteins. For many GPCRs, structurally related ligands can have diverse efficacy profiles. To investigate the process of ligand binding and activation, we used fluorescence spectroscopy to study the ability of ligands having different efficacies to induce a specific conformational change in the human beta2-adrenoceptor (beta2-AR). The 'ionic lock' is a molecular switch found in rhodopsin-family GPCRs that has been proposed to link the cytoplasmic ends of transmembrane domains 3 and 6 in the inactive state. We found that most partial agonists were as effective as full agonists in disrupting the ionic lock. Our results show that disruption of this important molecular switch is necessary, but not sufficient, for full activation of the beta2-AR.
|
Induction of lipolysis in mouse C3H10T1/2 assessed as glycerol concentration
|
Mus musculus
|
19.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of new inhibitor for PDE3 by virtual screening.
Year : 2011
Volume : 21
Issue : 6
First Page : 1617
Last Page : 1620
Authors : Kim KY, Lee H, Yoo SE, Kim SH, Kang NS.
Abstract : In this work, we tried to find a new scaffold for a PDE3 using virtual screening for the obesity treatment. We first analyzed structural features for the known PDE3 inhibitors based on the PDE3B-ligand complex structure, and then carried out a docking study based on PDE3B 3D structure. We obtained a compound as potent PDE3 inhibitor stimulating lipolysis in murine adipocytes and human adipocytes.
|
Agonist activity at human adrenergic beta2 receptor expressed in H292 cells assessed as intracellular cAMP accumulation after 1 hr
|
Homo sapiens
|
39.81
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design driven HtL: The discovery and synthesis of new high efficacy β₂-agonists.
Year : 2011
Volume : 21
Issue : 13
First Page : 4027
Last Page : 4031
Authors : Stocks MJ, Alcaraz L, Bailey A, Bonnert R, Cadogan E, Christie J, Connolly S, Cook A, Fisher A, Flaherty A, Hill S, Humphries A, Ingall A, Jordan S, Lawson M, Mullen A, Nicholls D, Paine S, Pairaudeau G, St-Gallay S, Young A.
Abstract : The design and synthesis of a new series of high efficacy β(2)-agonists devoid of the key benzylic alcohol present in previously described highly efficacious β(2)-agonists is reported. A hypothesis for the unprecedented level of efficacy is proposed based on considerations of β(2)-adrenoceptor crystal structure, other biophysical data and modeling studies.
|
Agonist activity at human adrenergic beta3 receptor expressed in CHO cells assessed as cAMP accumulation
|
Homo sapiens
|
39.81
nM
|
|
Journal : Bioorg. Med. Chem.
Title : The discovery of long-acting saligenin β₂ adrenergic receptor agonists incorporating hydantoin or uracil rings.
Year : 2011
Volume : 19
Issue : 14
First Page : 4192
Last Page : 4201
Authors : Procopiou PA, Barrett VJ, Bevan NJ, Butchers PR, Conroy R, Emmons A, Ford AJ, Jeulin S, Looker BE, Lunniss GE, Morrison VS, Mutch PJ, Perciaccante R, Ruston M, Smith CE, Somers G.
Abstract : A series of novel, potent and selective human β(2) adrenoceptor agonists incorporating a hydantoin or a uracil ring on the right-hand side phenyl ring of (R)-salmeterol is presented. Hydantoin 12a had long duration of action in vitro on guinea pig trachea, and 12h in guinea pigs in vivo at its EC(90) 25 μM. It had lower oral absorption than salmeterol in rats, and lower bioavailability than salmeterol in vivo in both rats and dogs (2% and 5%, respectively). An improved method for measuring the absorbed fraction of analogues dosed to rats, which considers the glucuronidated fraction is presented. Compound 12a was metabolised in human liver microsomes and hepatocytes to the active hydantoic acid 12m.
|
Agonist activity at human adrenergic beta1 receptor expressed in CHO cells assessed as cAMP accumulation
|
Homo sapiens
|
7.943
nM
|
|
Journal : Bioorg. Med. Chem.
Title : The discovery of long-acting saligenin β₂ adrenergic receptor agonists incorporating hydantoin or uracil rings.
Year : 2011
Volume : 19
Issue : 14
First Page : 4192
Last Page : 4201
Authors : Procopiou PA, Barrett VJ, Bevan NJ, Butchers PR, Conroy R, Emmons A, Ford AJ, Jeulin S, Looker BE, Lunniss GE, Morrison VS, Mutch PJ, Perciaccante R, Ruston M, Smith CE, Somers G.
Abstract : A series of novel, potent and selective human β(2) adrenoceptor agonists incorporating a hydantoin or a uracil ring on the right-hand side phenyl ring of (R)-salmeterol is presented. Hydantoin 12a had long duration of action in vitro on guinea pig trachea, and 12h in guinea pigs in vivo at its EC(90) 25 μM. It had lower oral absorption than salmeterol in rats, and lower bioavailability than salmeterol in vivo in both rats and dogs (2% and 5%, respectively). An improved method for measuring the absorbed fraction of analogues dosed to rats, which considers the glucuronidated fraction is presented. Compound 12a was metabolised in human liver microsomes and hepatocytes to the active hydantoic acid 12m.
|
Agonist activity at human adrenergic beta2 receptor expressed in CHO cells assessed as cAMP accumulation
|
Homo sapiens
|
39.81
nM
|
|
Journal : Bioorg. Med. Chem.
Title : The discovery of long-acting saligenin β₂ adrenergic receptor agonists incorporating hydantoin or uracil rings.
Year : 2011
Volume : 19
Issue : 14
First Page : 4192
Last Page : 4201
Authors : Procopiou PA, Barrett VJ, Bevan NJ, Butchers PR, Conroy R, Emmons A, Ford AJ, Jeulin S, Looker BE, Lunniss GE, Morrison VS, Mutch PJ, Perciaccante R, Ruston M, Smith CE, Somers G.
Abstract : A series of novel, potent and selective human β(2) adrenoceptor agonists incorporating a hydantoin or a uracil ring on the right-hand side phenyl ring of (R)-salmeterol is presented. Hydantoin 12a had long duration of action in vitro on guinea pig trachea, and 12h in guinea pigs in vivo at its EC(90) 25 μM. It had lower oral absorption than salmeterol in rats, and lower bioavailability than salmeterol in vivo in both rats and dogs (2% and 5%, respectively). An improved method for measuring the absorbed fraction of analogues dosed to rats, which considers the glucuronidated fraction is presented. Compound 12a was metabolised in human liver microsomes and hepatocytes to the active hydantoic acid 12m.
|
Agonist activity at human beta2 receptor expressed in CHO cells assessed as cAMP accumulation
|
Homo sapiens
|
39.81
nM
|
|
Journal : Bioorg. Med. Chem.
Title : The discovery of long-acting saligenin β₂ adrenergic receptor agonists incorporating a urea group.
Year : 2011
Volume : 19
Issue : 20
First Page : 6026
Last Page : 6032
Authors : Procopiou PA, Barrett VJ, Ford AJ, Looker BE, Lunniss GE, Needham D, Smith CE, Somers G.
Abstract : A series of novel, potent and selective human β(2) adrenoceptor agonists incorporating a urea moiety on the terminal right-hand side phenyl ring of (R)-salmeterol is presented. Urea 9j had long duration of action in vitro on guinea pig trachea, and also in vivo similar to that of salmeterol. It had lower oral absorption and bioavailability than salmeterol in both rat and dog. It had a turnover ratio similar to salmeterol, with no evidence for formation of any aniline metabolites in human liver microsomes and hepatocytes. However no crystalline salts suitable for inhaled delivery were identified.
|
Agonist activity at human beta1 receptor expressed in CHO cells assessed as cAMP accumulation
|
Homo sapiens
|
7.943
nM
|
|
Journal : Bioorg. Med. Chem.
Title : The discovery of long-acting saligenin β₂ adrenergic receptor agonists incorporating a urea group.
Year : 2011
Volume : 19
Issue : 20
First Page : 6026
Last Page : 6032
Authors : Procopiou PA, Barrett VJ, Ford AJ, Looker BE, Lunniss GE, Needham D, Smith CE, Somers G.
Abstract : A series of novel, potent and selective human β(2) adrenoceptor agonists incorporating a urea moiety on the terminal right-hand side phenyl ring of (R)-salmeterol is presented. Urea 9j had long duration of action in vitro on guinea pig trachea, and also in vivo similar to that of salmeterol. It had lower oral absorption and bioavailability than salmeterol in both rat and dog. It had a turnover ratio similar to salmeterol, with no evidence for formation of any aniline metabolites in human liver microsomes and hepatocytes. However no crystalline salts suitable for inhaled delivery were identified.
|
Agonist activity at human beta3 receptor expressed in CHO cells assessed as cAMP accumulation
|
Homo sapiens
|
39.81
nM
|
|
Journal : Bioorg. Med. Chem.
Title : The discovery of long-acting saligenin β₂ adrenergic receptor agonists incorporating a urea group.
Year : 2011
Volume : 19
Issue : 20
First Page : 6026
Last Page : 6032
Authors : Procopiou PA, Barrett VJ, Ford AJ, Looker BE, Lunniss GE, Needham D, Smith CE, Somers G.
Abstract : A series of novel, potent and selective human β(2) adrenoceptor agonists incorporating a urea moiety on the terminal right-hand side phenyl ring of (R)-salmeterol is presented. Urea 9j had long duration of action in vitro on guinea pig trachea, and also in vivo similar to that of salmeterol. It had lower oral absorption and bioavailability than salmeterol in both rat and dog. It had a turnover ratio similar to salmeterol, with no evidence for formation of any aniline metabolites in human liver microsomes and hepatocytes. However no crystalline salts suitable for inhaled delivery were identified.
|
DRUGMATRIX: Adrenergic beta1 radioligand binding (ligand: [125I] Cyanopindolol)
|
None
|
333.0
nM
|
|
DRUGMATRIX: Adrenergic beta1 radioligand binding (ligand: [125I] Cyanopindolol)
|
None
|
193.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Adrenergic beta2 radioligand binding (ligand: [3H] CGP-12177)
|
None
|
246.0
nM
|
|
DRUGMATRIX: Adrenergic beta2 radioligand binding (ligand: [3H] CGP-12177)
|
None
|
169.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
Agonist activity at beta2 adrenoceptor in guinea pig assessed as relaxation of histamine-induced tracheal ring contraction
|
Cavia porcellus
|
31.62
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Dual β2-adrenoceptor agonists-PDE4 inhibitors for the treatment of asthma and COPD.
Year : 2012
Volume : 22
Issue : 4
First Page : 1523
Last Page : 1526
Authors : Shan WJ, Huang L, Zhou Q, Jiang HL, Luo ZH, Lai KF, Li XS.
Abstract : We designed and synthesized a novel class of dual pharmacology bronchodilators targeting both β(2)-adrenoceptor and PDE4 by applying a multivalent approach. The most potent dual pharmacology molecule, compound 29, possessed good inhibitory activity on PDE4B2 (IC(50)=0.278 μM, which was more potent than phthalazinone, IC(50)=0.520 μM) and possessed excellent relaxant effects on tracheal rings precontracted by histamine (pEC(50)=9.3).
|
Agonist activity at beta2-adrenoceptor in guinea pig trachea assessed as relaxation of histamine-induced precontracted tracheal rings
|
Cavia porcellus
|
28.84
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Hybrids consisting of the pharmacophores of salmeterol and roflumilast or phthalazinone: dual β₂-adrenoceptor agonists-PDE4 inhibitors for the treatment of COPD.
Year : 2013
Volume : 23
Issue : 5
First Page : 1548
Last Page : 1552
Authors : Liu A, Huang L, Wang Z, Luo Z, Mao F, Shan W, Xie J, Lai K, Li X.
Abstract : A novel class of dual pharmacology bronchodilators targeting both β(2)-adrenoceptor and PDE4 was designed and synthesised by combining the pharmacophores of salmeterol and roflumilast or phthalazinone. All the compounds exhibited better β(2)-adrenoceptor agonist activities (pEC(50)=8.47-9.20) than the reference compound salmeterol (pEC(50)=8.3) and good inhibitory activity on PDE4B2 (IC(50)=0.235-1.093 μM).
|
Binding affinity to beta-2 adrenergic receptor (unknown origin) at 1 to 10000 nM
|
Homo sapiens
|
251.19
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : β2-Adrenoceptor agonists in the regulation of mitochondrial biogenesis.
Year : 2013
Volume : 23
Issue : 19
First Page : 5376
Last Page : 5381
Authors : Peterson YK, Cameron RB, Wills LP, Trager RE, Lindsey CC, Beeson CC, Schnellmann RG.
Abstract : The stimulation of mitochondrial biogenesis (MB) via cell surface G-protein coupled receptors is a promising strategy for cell repair and regeneration. Here we report the specificity and chemical rationale of a panel of β2-adrenoceptor agonists with regards to MB. Using primary cultures of renal cells, a diverse panel of β2-adrenoceptor agonists elicited three distinct phenotypes: full MB, partial MB, and non-MB. Full MB compounds had efficacy in the low nanomolar range and represent two chemical scaffolds containing three distinct chemical clusters. Interestingly, the MB phenotype did not correlate with reported receptor affinity or chemical similarity. Chemical clusters were then subjected to pharmacophore modeling creating two models with unique and distinct features, consisting of five conserved amongst full MB compounds were identified. The two discrete pharmacophore models were coalesced into a consensus pharmacophore with four unique features elucidating the spatial and chemical characteristics required to stimulate MB.
|
Agonist activity at guinea pig trachea beta2-adrenergic receptor assessed as relaxation of histamine-induced tracheal ring contraction
|
Cavia porcellus
|
31.62
nM
|
|
Agonist activity at guinea pig trachea beta2-adrenergic receptor assessed as relaxation of histamine-induced tracheal ring contraction
|
Cavia porcellus
|
31.64
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis and evaluation of dual pharmacology β2-adrenoceptor agonists and PDE4 inhibitors.
Year : 2014
Volume : 24
Issue : 1
First Page : 249
Last Page : 253
Authors : Huang L, Shan W, Zhou Q, Xie J, Lai K, Li X.
Abstract : A novel series of formoterol-phthalazinone hybrids were synthesised and evaluated as dual pharmacology β2-adrenoceptor agonists and PDE4 inhibitors. Most of the hybrids displayed high β2-adrenoceptor agonist and moderate PDE4 inhibitory activities. The most potent compound, (R,R)-11c, exhibited agonist (EC50=1.05nM, pEC50=9.0) and potent PDE4B2 inhibitory activities (IC50=0.092μM).
|
Agonist activity at human beta2 adrenergic receptor expressed in HEK293 cells assessed as stimulation of cAMP accumulation
|
Homo sapiens
|
0.2
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Comparative molecular field analysis of fenoterol derivatives interacting with an agonist-stabilized form of the β₂-adrenergic receptor.
Year : 2014
Volume : 22
Issue : 1
First Page : 234
Last Page : 246
Authors : Plazinska A, Pajak K, Rutkowska E, Jimenez L, Kozocas J, Koolpe G, Tanga M, Toll L, Wainer IW, Jozwiak K.
Abstract : The β₂-adrenergic receptor (β₂-AR) agonist [(3)H]-(R,R')-methoxyfenoterol was employed as the marker ligand in displacement studies measuring the binding affinities (Ki values) of the stereoisomers of a series of 4'-methoxyfenoterol analogs in which the length of the alkyl substituent at α' position was varied from 0 to 3 carbon atoms. The binding affinities of the compounds were additionally determined using the inverse agonist [(3)H]-CGP-12177 as the marker ligand and the ability of the compounds to stimulate cAMP accumulation, measured as EC₅₀ values, were determined in HEK293 cells expressing the β₂-AR. The data indicate that the highest binding affinities and functional activities were produced by methyl and ethyl substituents at the α' position. The results also indicate that the Ki values obtained using [(3)H]-(R,R')-methoxyfenoterol as the marker ligand modeled the EC₅₀ values obtained from cAMP stimulation better than the data obtained using [(3)H]-CGP-12177 as the marker ligand. The data from this study was combined with data from previous studies and processed using the Comparative Molecular Field Analysis approach to produce a CoMFA model reflecting the binding to the β₂-AR conformation probed by [(3)H]-(R,R')-4'-methoxyfenoterol. The CoMFA model of the agonist-stabilized β₂-AR suggests that the binding of the fenoterol analogs to an agonist-stabilized conformation of the β₂-AR is governed to a greater extend by steric effects than binding to the [(3)H]-CGP-12177-stabilized conformation(s) in which electrostatic interactions play a more predominate role.
|
Displacement of [3H]-(R,R')-methoxyfenoterol from human beta2 adrenergic receptor expressed in HEK cells by liquid scintillation counting analysis
|
Homo sapiens
|
2.44
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Comparative molecular field analysis of fenoterol derivatives interacting with an agonist-stabilized form of the β₂-adrenergic receptor.
Year : 2014
Volume : 22
Issue : 1
First Page : 234
Last Page : 246
Authors : Plazinska A, Pajak K, Rutkowska E, Jimenez L, Kozocas J, Koolpe G, Tanga M, Toll L, Wainer IW, Jozwiak K.
Abstract : The β₂-adrenergic receptor (β₂-AR) agonist [(3)H]-(R,R')-methoxyfenoterol was employed as the marker ligand in displacement studies measuring the binding affinities (Ki values) of the stereoisomers of a series of 4'-methoxyfenoterol analogs in which the length of the alkyl substituent at α' position was varied from 0 to 3 carbon atoms. The binding affinities of the compounds were additionally determined using the inverse agonist [(3)H]-CGP-12177 as the marker ligand and the ability of the compounds to stimulate cAMP accumulation, measured as EC₅₀ values, were determined in HEK293 cells expressing the β₂-AR. The data indicate that the highest binding affinities and functional activities were produced by methyl and ethyl substituents at the α' position. The results also indicate that the Ki values obtained using [(3)H]-(R,R')-methoxyfenoterol as the marker ligand modeled the EC₅₀ values obtained from cAMP stimulation better than the data obtained using [(3)H]-CGP-12177 as the marker ligand. The data from this study was combined with data from previous studies and processed using the Comparative Molecular Field Analysis approach to produce a CoMFA model reflecting the binding to the β₂-AR conformation probed by [(3)H]-(R,R')-4'-methoxyfenoterol. The CoMFA model of the agonist-stabilized β₂-AR suggests that the binding of the fenoterol analogs to an agonist-stabilized conformation of the β₂-AR is governed to a greater extend by steric effects than binding to the [(3)H]-CGP-12177-stabilized conformation(s) in which electrostatic interactions play a more predominate role.
|
Displacement of [3H]-CGP-12177 from human beta2 adrenergic receptor expressed in HEK cells by liquid scintillation counting analysis
|
Homo sapiens
|
192.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Comparative molecular field analysis of fenoterol derivatives interacting with an agonist-stabilized form of the β₂-adrenergic receptor.
Year : 2014
Volume : 22
Issue : 1
First Page : 234
Last Page : 246
Authors : Plazinska A, Pajak K, Rutkowska E, Jimenez L, Kozocas J, Koolpe G, Tanga M, Toll L, Wainer IW, Jozwiak K.
Abstract : The β₂-adrenergic receptor (β₂-AR) agonist [(3)H]-(R,R')-methoxyfenoterol was employed as the marker ligand in displacement studies measuring the binding affinities (Ki values) of the stereoisomers of a series of 4'-methoxyfenoterol analogs in which the length of the alkyl substituent at α' position was varied from 0 to 3 carbon atoms. The binding affinities of the compounds were additionally determined using the inverse agonist [(3)H]-CGP-12177 as the marker ligand and the ability of the compounds to stimulate cAMP accumulation, measured as EC₅₀ values, were determined in HEK293 cells expressing the β₂-AR. The data indicate that the highest binding affinities and functional activities were produced by methyl and ethyl substituents at the α' position. The results also indicate that the Ki values obtained using [(3)H]-(R,R')-methoxyfenoterol as the marker ligand modeled the EC₅₀ values obtained from cAMP stimulation better than the data obtained using [(3)H]-CGP-12177 as the marker ligand. The data from this study was combined with data from previous studies and processed using the Comparative Molecular Field Analysis approach to produce a CoMFA model reflecting the binding to the β₂-AR conformation probed by [(3)H]-(R,R')-4'-methoxyfenoterol. The CoMFA model of the agonist-stabilized β₂-AR suggests that the binding of the fenoterol analogs to an agonist-stabilized conformation of the β₂-AR is governed to a greater extend by steric effects than binding to the [(3)H]-CGP-12177-stabilized conformation(s) in which electrostatic interactions play a more predominate role.
|
Antiallergic activity in antiovalbumin serum sensitized guinea pig lung slices assessed as inhibition of ovalbumin-induced histamine release at 0.3 uM preincubated for 5 mins followed by ovalbumin challenge measured after 15 mins by fluorometric analysis relative to control
|
Cavia porcellus
|
49.0
%
|
|
Journal : J. Med. Chem.
Title : Drug-induced modifications of the immune response. 1. Substituted 1-phenylisoquinolines.
Year : 1979
Volume : 22
Issue : 4
First Page : 348
Last Page : 352
Authors : St Georgiev V, Carlson RP, Van Inwegen RG, Khandwala A.
Abstract : A series of 1-phenylisoquinolines and related compounds was prepared and tested for potential antiallergic activity. Several compounds of this series inhibited the antigen-induced wheal formation in rat passive cutaneous anaphylaxis (PCA) assay, a commonly used test for antiallergic activity. Many of these compounds also inhibited the antigen-induced histamine release from passively sensitized guinea pig lung slices. Furthermore, almost all of these derivatives inhibited the cyclic nucleotide phosphodiesterase, suggesting this as one of several possible mechanisms of action.
|
Bronchodilator activity in dog assessed as degree of inhibition of carbachol or histamine-induced bronchoconstriction at 0.3 to 2 mg/kg, iv relative to control
|
Canis lupus familiaris
|
70.0
%
|
|
Journal : J. Med. Chem.
Title : Esters of N-tert-butylarterenol. Long-acting new bronchodilators with reduced cardiac effects.
Year : 1976
Volume : 19
Issue : 6
First Page : 834
Last Page : 838
Authors : Tullar BF, Minatoya H, Lorenz RR.
Abstract : The preparation of various esters of N-tert-butylarterenol is described. Esterification of the phenolic OH groups has increased bioavailability, prolonged bronchodilation, and reduced tachycardia. The substitution of aromatic esters compared with simple aliphatic esters improved markedly these pharmacological properties. Of a number of esters tested, compound 45 (bitolterol) demonstrated the most favorable pharmacological properties as a bronchodilator. Its long duration of action and significant bronchodilator-cardiovascular separation are briefly described.
|
Bronchodilator activity in dog assessed as degree of inhibition of carbachol or histamine-induced bronchoconstriction at 50 to 240 mg/kg, id relative to control
|
Canis lupus familiaris
|
20.0
%
|
|
Journal : J. Med. Chem.
Title : Esters of N-tert-butylarterenol. Long-acting new bronchodilators with reduced cardiac effects.
Year : 1976
Volume : 19
Issue : 6
First Page : 834
Last Page : 838
Authors : Tullar BF, Minatoya H, Lorenz RR.
Abstract : The preparation of various esters of N-tert-butylarterenol is described. Esterification of the phenolic OH groups has increased bioavailability, prolonged bronchodilation, and reduced tachycardia. The substitution of aromatic esters compared with simple aliphatic esters improved markedly these pharmacological properties. Of a number of esters tested, compound 45 (bitolterol) demonstrated the most favorable pharmacological properties as a bronchodilator. Its long duration of action and significant bronchodilator-cardiovascular separation are briefly described.
|
Bronchodilator activity in dog assessed as degree of inhibition of carbachol or histamine-induced bronchoconstriction at 125 to 250 mg/kg, it relative to control
|
Canis lupus familiaris
|
70.0
%
|
|
Journal : J. Med. Chem.
Title : Esters of N-tert-butylarterenol. Long-acting new bronchodilators with reduced cardiac effects.
Year : 1976
Volume : 19
Issue : 6
First Page : 834
Last Page : 838
Authors : Tullar BF, Minatoya H, Lorenz RR.
Abstract : The preparation of various esters of N-tert-butylarterenol is described. Esterification of the phenolic OH groups has increased bioavailability, prolonged bronchodilation, and reduced tachycardia. The substitution of aromatic esters compared with simple aliphatic esters improved markedly these pharmacological properties. Of a number of esters tested, compound 45 (bitolterol) demonstrated the most favorable pharmacological properties as a bronchodilator. Its long duration of action and significant bronchodilator-cardiovascular separation are briefly described.
|
Agonist activity at adrenergic beta2 receptor in Hartley guinea pig tracheal ring at basal tone assessed as bronchorelaxation activity
|
Cavia porcellus
|
25.12
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Insights on the role of boron containing moieties in the design of new potent and efficient agonists targeting the β2 adrenoceptor.
Year : 2015
Volume : 25
Issue : 4
First Page : 820
Last Page : 825
Authors : Soriano-Ursúa MA, Arias-Montaño JA, Correa-Basurto J, Hernández-Martínez CF, López-Cabrera Y, Castillo-Hernández MC, Padilla-Martínez II, Trujillo-Ferrara JG.
Abstract : The development of β2 adrenoceptor (β2AR) agonists is of increasing interest because of their wide-ranging applications in medicine, particularly for the treatment of pulmonary diseases. Regarding the relaxation of smooth muscle that lines airways of mammals, some boron-containing adducts have demonstrated greater potency and efficacy compared to well-known boron-free compounds. We herein report the design and synthesis as well as the chemical and pharmacological characterization of a new boron-containing compound: ((R)-6-((S)-2-(tert-butylammonio)-1-hydroxyethyl)-2-hydroxy-2-isobutyl-4H-benzo[d][1,3,2] dioxaborinin-2-uide). Compared to its precursor (salbutamol), this compound induced relaxation of smooth muscle in guinea pig tracheal rings with greater potency and efficacy (EC50⩽28.02nM). Theoretical studies suggest the potential selectivity of this boron containing compound on the orthosteric site of beta adrenoceptors and/or signaling pathways, as well as the importance of the tetracoordinated boron atom in its structure for binding recognition properties.
|
Agonist activity at adrenergic beta2 receptor in Hartley guinea pig tracheal ring assessed as bronchorelaxation activity against histamine-induced contraction
|
Cavia porcellus
|
17.78
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Insights on the role of boron containing moieties in the design of new potent and efficient agonists targeting the β2 adrenoceptor.
Year : 2015
Volume : 25
Issue : 4
First Page : 820
Last Page : 825
Authors : Soriano-Ursúa MA, Arias-Montaño JA, Correa-Basurto J, Hernández-Martínez CF, López-Cabrera Y, Castillo-Hernández MC, Padilla-Martínez II, Trujillo-Ferrara JG.
Abstract : The development of β2 adrenoceptor (β2AR) agonists is of increasing interest because of their wide-ranging applications in medicine, particularly for the treatment of pulmonary diseases. Regarding the relaxation of smooth muscle that lines airways of mammals, some boron-containing adducts have demonstrated greater potency and efficacy compared to well-known boron-free compounds. We herein report the design and synthesis as well as the chemical and pharmacological characterization of a new boron-containing compound: ((R)-6-((S)-2-(tert-butylammonio)-1-hydroxyethyl)-2-hydroxy-2-isobutyl-4H-benzo[d][1,3,2] dioxaborinin-2-uide). Compared to its precursor (salbutamol), this compound induced relaxation of smooth muscle in guinea pig tracheal rings with greater potency and efficacy (EC50⩽28.02nM). Theoretical studies suggest the potential selectivity of this boron containing compound on the orthosteric site of beta adrenoceptors and/or signaling pathways, as well as the importance of the tetracoordinated boron atom in its structure for binding recognition properties.
|
Agonist activity at human recombinant beta3-adrenergic receptor expressed in CHO cells assessed as increase of cAMP level after 30 mins
|
Homo sapiens
|
86.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of Novel Indazole Derivatives as Highly Potent and Selective Human β3-Adrenergic Receptor Agonists with the Possibility of Having No Cardiovascular Side Effects.
Year : 2015
Volume : 58
Issue : 15
First Page : 6048
Last Page : 6057
Authors : Wada Y, Shirahashi H, Iwanami T, Ogawa M, Nakano S, Morimoto A, Kasahara K, Tanaka E, Takada Y, Ohashi S, Mori M, Shuto S.
Abstract : Novel indazole derivatives were prepared and evaluated for their biological activity and cardiovascular safety profile as human β3-adrenergic receptor (AR) agonists. Although the initial hit compound 5 exhibited significant β3-AR agonistic activity (EC50 = 21 nM), it also exhibited agonistic activity at the α1A-AR (EC50 = 219 nM, selectivity: α1A/β3 = 10-fold). The major metabolite of 5, which was an oxidative product at the indazole 3-methyl moiety, gave a clue to a strategy for improvement of the selectivity for β3-AR agonistic activity versus α1A-AR agonistic activity. Thus, modification of the 3-substituent of the indazole moiety effectively improved the selectivity to develop compound 11 with potent β3-AR agonistic activity (EC50 = 13 nM) and high selectivity (α1A/β3 = >769-fold). Compound 11 was also inactive toward β1 and β2-ARs and showed dose dependent β3-AR mediated relaxation of marmoset urinary bladder smooth muscle, while it did not obviously affect heart rate or blood pressure (iv, 3 mg/kg) in anesthetized rats.
|
Displacement of [3H]CGP12177 from mouse beta1 receptor expressed in HEK293 cells
|
Mus musculus
|
220.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Structure-guided development of dual β2 adrenergic/dopamine D2 receptor agonists.
Year : 2016
Volume : 24
Issue : 12
First Page : 2641
Last Page : 2653
Authors : Weichert D, Stanek M, Hübner H, Gmeiner P.
Abstract : Aiming to discover dual-acting β2 adrenergic/dopamine D2 receptor ligands, a structure-guided approach for the evolution of GPCR agonists that address multiple targets was elaborated. Starting from GPCR crystal structures, we describe the design, synthesis and biological investigation of a defined set of compounds leading to the identification of the benzoxazinone (R)-3, which shows agonist properties at the adrenergic β2 receptor and substantial G protein-promoted activation at the D2 receptor. This directed approach yielded molecular probes with tuned dual activity. The congener desOH-3 devoid of the benzylic hydroxyl function was shown to be a β2 adrenergic antagonist/D2 receptor agonist with Ki values in the low nanomolar range. The compounds may serve as a promising starting point for the investigation and treatment of neurological disorders.
|
Displacement of [3H]CGP12177 from human beta2 receptor expressed in CHO cells
|
Homo sapiens
|
46.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Structure-guided development of dual β2 adrenergic/dopamine D2 receptor agonists.
Year : 2016
Volume : 24
Issue : 12
First Page : 2641
Last Page : 2653
Authors : Weichert D, Stanek M, Hübner H, Gmeiner P.
Abstract : Aiming to discover dual-acting β2 adrenergic/dopamine D2 receptor ligands, a structure-guided approach for the evolution of GPCR agonists that address multiple targets was elaborated. Starting from GPCR crystal structures, we describe the design, synthesis and biological investigation of a defined set of compounds leading to the identification of the benzoxazinone (R)-3, which shows agonist properties at the adrenergic β2 receptor and substantial G protein-promoted activation at the D2 receptor. This directed approach yielded molecular probes with tuned dual activity. The congener desOH-3 devoid of the benzylic hydroxyl function was shown to be a β2 adrenergic antagonist/D2 receptor agonist with Ki values in the low nanomolar range. The compounds may serve as a promising starting point for the investigation and treatment of neurological disorders.
|
Agonist activity at human beta2 receptor expressed in HEK293 cells cotransfected with Gqs5 protein assessed as [3H]IP3 accumulation after 120 mins by scintillation counting assay in presence of myo-[3H]-inositol
|
Homo sapiens
|
87.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Structure-guided development of dual β2 adrenergic/dopamine D2 receptor agonists.
Year : 2016
Volume : 24
Issue : 12
First Page : 2641
Last Page : 2653
Authors : Weichert D, Stanek M, Hübner H, Gmeiner P.
Abstract : Aiming to discover dual-acting β2 adrenergic/dopamine D2 receptor ligands, a structure-guided approach for the evolution of GPCR agonists that address multiple targets was elaborated. Starting from GPCR crystal structures, we describe the design, synthesis and biological investigation of a defined set of compounds leading to the identification of the benzoxazinone (R)-3, which shows agonist properties at the adrenergic β2 receptor and substantial G protein-promoted activation at the D2 receptor. This directed approach yielded molecular probes with tuned dual activity. The congener desOH-3 devoid of the benzylic hydroxyl function was shown to be a β2 adrenergic antagonist/D2 receptor agonist with Ki values in the low nanomolar range. The compounds may serve as a promising starting point for the investigation and treatment of neurological disorders.
|
Agonist activity at PK-tagged beta2 receptor (unknown origin) transfected in HEK293 cells after 90 mins by beta-arrestin assay
|
Homo sapiens
|
120.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Structure-guided development of dual β2 adrenergic/dopamine D2 receptor agonists.
Year : 2016
Volume : 24
Issue : 12
First Page : 2641
Last Page : 2653
Authors : Weichert D, Stanek M, Hübner H, Gmeiner P.
Abstract : Aiming to discover dual-acting β2 adrenergic/dopamine D2 receptor ligands, a structure-guided approach for the evolution of GPCR agonists that address multiple targets was elaborated. Starting from GPCR crystal structures, we describe the design, synthesis and biological investigation of a defined set of compounds leading to the identification of the benzoxazinone (R)-3, which shows agonist properties at the adrenergic β2 receptor and substantial G protein-promoted activation at the D2 receptor. This directed approach yielded molecular probes with tuned dual activity. The congener desOH-3 devoid of the benzylic hydroxyl function was shown to be a β2 adrenergic antagonist/D2 receptor agonist with Ki values in the low nanomolar range. The compounds may serve as a promising starting point for the investigation and treatment of neurological disorders.
|
Agonist activity at recombinant human beta3 adrenergic receptor expressed in CHO cells assessed as accumulation of cyclic AMP after 30 mins
|
Homo sapiens
|
86.0
nM
|
|
Journal : J Med Chem
Title : Discovery of Novel Indazole Derivatives as Orally Available β3-Adrenergic Receptor Agonists Lacking Off-Target-Based Cardiovascular Side Effects.
Year : 2017
Volume : 60
Issue : 8
First Page : 3252
Last Page : 3265
Authors : Wada Y, Nakano S, Morimoto A, Kasahara KI, Hayashi T, Takada Y, Suzuki H, Niwa-Sakai M, Ohashi S, Mori M, Hirokawa T, Shuto S.
Abstract : We previously discovered that indazole derivative 8 was a highly selective β3-adrenergic receptor (β3-AR) agonist, but it appeared to be metabolically unstable. To improve metabolic stability, further optimization of this scaffold was carried out. We focused on the sulfonamide moiety of this scaffold, which resulted in the discovery of compound 15 as a highly potent β3-AR agonist (EC50 = 18 nM) being inactive to β1-, β2-, and α1A-AR (β1/β3, β2/β3, and α1A/β3 > 556-fold). Compound 15 showed dose-dependent β3-AR-mediated responses in marmoset urinary bladder smooth muscle, had a desirable metabolic stability and pharmacokinetic profile (Cmax and AUC), and did not obviously affect heart rate or mean blood pressure when administered intravenously (3 mg/kg) to anesthetized rats. Thus, compound 15 is a highly potent, selective, and orally available β3-AR agonist, which may serve as a candidate drug for the treatment of overactive bladder without off-target-based cardiovascular side effects.
|
Agonist activity at recombinant human beta1 adrenergic receptor expressed in CHO cells assessed as accumulation of cyclic AMP after 30 mins
|
Homo sapiens
|
3.2
nM
|
|
Journal : J Med Chem
Title : Discovery of Novel Indazole Derivatives as Orally Available β3-Adrenergic Receptor Agonists Lacking Off-Target-Based Cardiovascular Side Effects.
Year : 2017
Volume : 60
Issue : 8
First Page : 3252
Last Page : 3265
Authors : Wada Y, Nakano S, Morimoto A, Kasahara KI, Hayashi T, Takada Y, Suzuki H, Niwa-Sakai M, Ohashi S, Mori M, Hirokawa T, Shuto S.
Abstract : We previously discovered that indazole derivative 8 was a highly selective β3-adrenergic receptor (β3-AR) agonist, but it appeared to be metabolically unstable. To improve metabolic stability, further optimization of this scaffold was carried out. We focused on the sulfonamide moiety of this scaffold, which resulted in the discovery of compound 15 as a highly potent β3-AR agonist (EC50 = 18 nM) being inactive to β1-, β2-, and α1A-AR (β1/β3, β2/β3, and α1A/β3 > 556-fold). Compound 15 showed dose-dependent β3-AR-mediated responses in marmoset urinary bladder smooth muscle, had a desirable metabolic stability and pharmacokinetic profile (Cmax and AUC), and did not obviously affect heart rate or mean blood pressure when administered intravenously (3 mg/kg) to anesthetized rats. Thus, compound 15 is a highly potent, selective, and orally available β3-AR agonist, which may serve as a candidate drug for the treatment of overactive bladder without off-target-based cardiovascular side effects.
|
Agonist activity at recombinant human beta2 adrenergic receptor expressed in CHO cells assessed as accumulation of cyclic AMP after 30 mins
|
Homo sapiens
|
13.0
nM
|
|
Journal : J Med Chem
Title : Discovery of Novel Indazole Derivatives as Orally Available β3-Adrenergic Receptor Agonists Lacking Off-Target-Based Cardiovascular Side Effects.
Year : 2017
Volume : 60
Issue : 8
First Page : 3252
Last Page : 3265
Authors : Wada Y, Nakano S, Morimoto A, Kasahara KI, Hayashi T, Takada Y, Suzuki H, Niwa-Sakai M, Ohashi S, Mori M, Hirokawa T, Shuto S.
Abstract : We previously discovered that indazole derivative 8 was a highly selective β3-adrenergic receptor (β3-AR) agonist, but it appeared to be metabolically unstable. To improve metabolic stability, further optimization of this scaffold was carried out. We focused on the sulfonamide moiety of this scaffold, which resulted in the discovery of compound 15 as a highly potent β3-AR agonist (EC50 = 18 nM) being inactive to β1-, β2-, and α1A-AR (β1/β3, β2/β3, and α1A/β3 > 556-fold). Compound 15 showed dose-dependent β3-AR-mediated responses in marmoset urinary bladder smooth muscle, had a desirable metabolic stability and pharmacokinetic profile (Cmax and AUC), and did not obviously affect heart rate or mean blood pressure when administered intravenously (3 mg/kg) to anesthetized rats. Thus, compound 15 is a highly potent, selective, and orally available β3-AR agonist, which may serve as a candidate drug for the treatment of overactive bladder without off-target-based cardiovascular side effects.
|
Agonist activity at human beta2-AR expressed in CHOK1 cells co-expressing Galpha15 measured after 21 secs to 120 secs by Calcium-4 dye based FLIPR assay
|
Homo sapiens
|
0.7
nM
|
|
Journal : J Nat Prod
Title : Catecholic Isoquinolines from Portulaca oleracea and Their Anti-inflammatory and β2-Adrenergic Receptor Agonist Activity.
Year : 2018
Volume : 81
Issue : 4
First Page : 768
Last Page : 777
Authors : Jin TY, Li SQ, Jin CR, Shan H, Wang RM, Zhou MX, Li AL, Li LY, Hu SY, Shen T, Xiang L.
Abstract : Isoquinoline alkaloids possess a wide range of structural features and pharmaceutical activities and are promising drug candidates. Ten water-soluble catecholic isoquinolines were isolated from the medicinal plant Portulaca oleracea, including three new (1-3) and seven known compounds (4-10), along with the known catecholamines 11 and 12 and four other known compounds (13-16). A method of polyamide column chromatography using EtOAc-MeOH as the mobile phase was developed for the isolation of catecholic isoquinolines. Alkaloids 1-12 exhibited anti-inflammatory activities (EC50 = 18.0-497.7 μM) through inhibition of NO production in lipopolysaccharide-induced murine macrophage RAW 264.7 cells. Among these compounds, 11, 2, 5, 4, and 8 were more potent than was the positive control, 3,4-dihydroxybenzohydroxamic acid (EC50 = 82.4 μM), with EC50 values of 18.0, 18.1, 35.4, 36.3, and 58.7 μM, respectively. Additionally, at 100 μM, compounds 1-12 showed different degrees of β2-adrenergic receptor (β2-AR) agonist activity in the CHO-K1/GA15 cell line which stably expressed β2-AR as detected by a calcium assay. The EC50 values of 2 and 10 were 5.1 μM and 87.9 nM, respectively.
|
Agonist activity at human beta2 adrenergic receptor expressed in HEK293 cells assessed as increase in cAMP accumulation after 60 mins by HTRF assay
|
Homo sapiens
|
0.3162
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis and biological evaluation of β2-adrenoceptor agonists bearing the 2-amino-2-phenylethanol scaffold.
Year : 2018
Volume : 152
First Page : 424
Last Page : 435
Authors : Ge X, Woo AY, Xing G, Lu Y, Mo Y, Zhao Y, Lan Y, Li J, Yan H, Pan L, Zhang Y, Lin B, Cheng M.
Abstract : A new series of β2-adrenoceptor agonists bearing the 2-amino-2-phenylethanol scaffold was synthesized. Evaluation of the compounds using cell assays and an in vitro guinea pig trachea relaxation assay showed that 8-hydroxy-5-(2-hydroxy-1-((4-hydroxyphenethyl)amino)ethyl)quinolin-2(1H)-one (compound 5j) has the best pharmacological profile among all the evaluated compounds. The (S)-isomer of 5j was subsequently found to be the active enantiomer with a promising EC50 value of 1.26 nM in stimulating β2-adrenoceptor-mediated cAMP accumulation and a substantially higher selectivity for the β2 than for the β1 subtype. The putative binding mode of (S)-5j revealed by molecular docking of the β2-adrenoceptor resembles that in agonist binding. Taken together, these results showed that compound (S)-5j is a promising compound worthy of further study for the development of β2-adrenoceptor agonists.
|
Agonist activity at human beta1 adrenergic receptor expressed in HEK293 cells assessed as increase in cAMP accumulation after 60 mins by HTRF assay
|
Homo sapiens
|
3.162
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis and biological evaluation of β2-adrenoceptor agonists bearing the 2-amino-2-phenylethanol scaffold.
Year : 2018
Volume : 152
First Page : 424
Last Page : 435
Authors : Ge X, Woo AY, Xing G, Lu Y, Mo Y, Zhao Y, Lan Y, Li J, Yan H, Pan L, Zhang Y, Lin B, Cheng M.
Abstract : A new series of β2-adrenoceptor agonists bearing the 2-amino-2-phenylethanol scaffold was synthesized. Evaluation of the compounds using cell assays and an in vitro guinea pig trachea relaxation assay showed that 8-hydroxy-5-(2-hydroxy-1-((4-hydroxyphenethyl)amino)ethyl)quinolin-2(1H)-one (compound 5j) has the best pharmacological profile among all the evaluated compounds. The (S)-isomer of 5j was subsequently found to be the active enantiomer with a promising EC50 value of 1.26 nM in stimulating β2-adrenoceptor-mediated cAMP accumulation and a substantially higher selectivity for the β2 than for the β1 subtype. The putative binding mode of (S)-5j revealed by molecular docking of the β2-adrenoceptor resembles that in agonist binding. Taken together, these results showed that compound (S)-5j is a promising compound worthy of further study for the development of β2-adrenoceptor agonists.
|
Agonist activity at human beta3 adrenergic receptor expressed in HEK293 cells assessed as increase in cAMP accumulation after 60 mins by HTRF assay
|
Homo sapiens
|
53.7
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis and biological evaluation of β2-adrenoceptor agonists bearing the 2-amino-2-phenylethanol scaffold.
Year : 2018
Volume : 152
First Page : 424
Last Page : 435
Authors : Ge X, Woo AY, Xing G, Lu Y, Mo Y, Zhao Y, Lan Y, Li J, Yan H, Pan L, Zhang Y, Lin B, Cheng M.
Abstract : A new series of β2-adrenoceptor agonists bearing the 2-amino-2-phenylethanol scaffold was synthesized. Evaluation of the compounds using cell assays and an in vitro guinea pig trachea relaxation assay showed that 8-hydroxy-5-(2-hydroxy-1-((4-hydroxyphenethyl)amino)ethyl)quinolin-2(1H)-one (compound 5j) has the best pharmacological profile among all the evaluated compounds. The (S)-isomer of 5j was subsequently found to be the active enantiomer with a promising EC50 value of 1.26 nM in stimulating β2-adrenoceptor-mediated cAMP accumulation and a substantially higher selectivity for the β2 than for the β1 subtype. The putative binding mode of (S)-5j revealed by molecular docking of the β2-adrenoceptor resembles that in agonist binding. Taken together, these results showed that compound (S)-5j is a promising compound worthy of further study for the development of β2-adrenoceptor agonists.
|
Agonist activity at human beta2 adrenergic receptor expressed in HEK293 cells assessed as increase in cAMP accumulation after 60 mins by HTRF assay
|
Homo sapiens
|
0.3162
nM
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis and biological evaluation of 5-(2-amino-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one derivatives as potent β<sub>2</sub>-adrenoceptor agonists.
Year : 2019
Volume : 27
Issue : 12
First Page : 2306
Last Page : 2314
Authors : Xing G, Pan L, Yi C, Li X, Ge X, Zhao Y, Liu Y, Li J, Woo A, Lin B, Zhang Y, Cheng M.
Abstract : A series of novel β<sub>2</sub>-adrenoceptor agonists with a 5-(2-amino-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one moiety was designed, synthesized and evaluated for biological activity in human embryonic kidney 293 cells and isolated guinea pig trachea. Compounds 9g and (R)-18c exhibited the most excellent β<sub>2</sub>-adrenoceptor agonistic effects and high β<sub>2</sub>/β<sub>1</sub>-selectivity with EC<sub>50</sub> values of 36 pM for 9g and 21 pM for (R)-18c. They produced potent airway smooth muscle relaxant effects with fast onset of action and long duration of action in an in vitro guinea pig trachea model of bronchodilation. These results support further development of the two compounds into drug candidates.
|
Agonist activity at human beta1 adrenergic receptor expressed in HEK293 cells assessed as increase in cAMP accumulation after 60 mins by HTRF assay
|
Homo sapiens
|
3.162
nM
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis and biological evaluation of 5-(2-amino-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one derivatives as potent β<sub>2</sub>-adrenoceptor agonists.
Year : 2019
Volume : 27
Issue : 12
First Page : 2306
Last Page : 2314
Authors : Xing G, Pan L, Yi C, Li X, Ge X, Zhao Y, Liu Y, Li J, Woo A, Lin B, Zhang Y, Cheng M.
Abstract : A series of novel β<sub>2</sub>-adrenoceptor agonists with a 5-(2-amino-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one moiety was designed, synthesized and evaluated for biological activity in human embryonic kidney 293 cells and isolated guinea pig trachea. Compounds 9g and (R)-18c exhibited the most excellent β<sub>2</sub>-adrenoceptor agonistic effects and high β<sub>2</sub>/β<sub>1</sub>-selectivity with EC<sub>50</sub> values of 36 pM for 9g and 21 pM for (R)-18c. They produced potent airway smooth muscle relaxant effects with fast onset of action and long duration of action in an in vitro guinea pig trachea model of bronchodilation. These results support further development of the two compounds into drug candidates.
|
Agonist activity at human beta2 adrenergic receptor expressed in CHOK1 cells co-expressing Galpha15 assessed as increase in calcium influx by measuring fluorescence intensity by FLIPR assay
|
Homo sapiens
|
1.2
nM
|
|
Journal : J Nat Prod
Title : Synthesis, Purification, and Selective β2-AR Agonist and Bronchodilatory Effects of Catecholic Tetrahydroisoquinolines from Portulaca oleracea.
Year : 2019
Volume : 82
Issue : 11
First Page : 2986
Last Page : 2993
Authors : Yang EL, Sun B, Huang ZY, Lin JG, Jiao B, Xiang L.
Abstract : A green, biomimetic, phosphate-mediated Pictet-Spengler reaction was used in the synthesis of three catecholic tetrahydroisoquinolines, 1, 2, and 12, present in the medicinal plant Portulaca oleracea, as well as their analogues 3-11, 13, and 14, with dopamine hydrochloride and aldehydes as the substrates. AB-8 macroporous resin column chromatography was applied for purification of the products from the one-step high-efficacy synthesis. It eliminated the difficulties in the isolation of catecholic tetrahydroisoquinolines from the aqueous reaction system and unreacted dopamine hydrochloride. Activity screening in CHO-K1/Gα15 cell models consistently expressing α1B-, β1-, or β2-adrenergic receptors indicated that 12 and 2, compounds that are present in P. oleracea, possessed the most potent β2-adrenergic receptor agonist activity and 2 was a selective β2-adrenergic receptor agonist at the concentration of 100 μM. Both 12 and 2 exhibited dose-dependent bronchodilator effects on the histamine-induced contraction of isolated guinea-pig tracheal smooth muscle, with EC50 values of 0.8 and 2.8 μM, respectively. These findings explain the scientific rationale of P. oleracea use as an antiasthmatic herb in folk medicine and provide the basis for the discovery of novel antiasthma drugs.
|
Agonist activity at beta2 adrenergic receptor in guinea pig tracheal smooth muscle assessed as inhibition of histamine-induced tracheal smooth muscle contraction by measuring spasmolysis preincubated for 15 mins in presence of beta adrenergic receptor antagonist propranolol followed by histamine addition
|
Cavia porcellus
|
7.9
nM
|
|
Journal : J Nat Prod
Title : Synthesis, Purification, and Selective β2-AR Agonist and Bronchodilatory Effects of Catecholic Tetrahydroisoquinolines from Portulaca oleracea.
Year : 2019
Volume : 82
Issue : 11
First Page : 2986
Last Page : 2993
Authors : Yang EL, Sun B, Huang ZY, Lin JG, Jiao B, Xiang L.
Abstract : A green, biomimetic, phosphate-mediated Pictet-Spengler reaction was used in the synthesis of three catecholic tetrahydroisoquinolines, 1, 2, and 12, present in the medicinal plant Portulaca oleracea, as well as their analogues 3-11, 13, and 14, with dopamine hydrochloride and aldehydes as the substrates. AB-8 macroporous resin column chromatography was applied for purification of the products from the one-step high-efficacy synthesis. It eliminated the difficulties in the isolation of catecholic tetrahydroisoquinolines from the aqueous reaction system and unreacted dopamine hydrochloride. Activity screening in CHO-K1/Gα15 cell models consistently expressing α1B-, β1-, or β2-adrenergic receptors indicated that 12 and 2, compounds that are present in P. oleracea, possessed the most potent β2-adrenergic receptor agonist activity and 2 was a selective β2-adrenergic receptor agonist at the concentration of 100 μM. Both 12 and 2 exhibited dose-dependent bronchodilator effects on the histamine-induced contraction of isolated guinea-pig tracheal smooth muscle, with EC50 values of 0.8 and 2.8 μM, respectively. These findings explain the scientific rationale of P. oleracea use as an antiasthmatic herb in folk medicine and provide the basis for the discovery of novel antiasthma drugs.
|
Agonist activity at human TAS2R1 expressed in HEK293T cells co-expressing Galpha15 assessed as increase in intracellular calcium level by Calcium-3 dye based fluorescence assay
|
Homo sapiens
|
4.9
nM
|
|
Title : Assays for identifying compounds that modulate bitter taste
|
Agonist activity at human TAS2R8 expressed in HEK293T cells co-expressing Galpha15 assessed as increase in intracellular calcium level by Calcium-3 dye based fluorescence assay
|
Homo sapiens
|
4.9
nM
|
|
Title : Assays for identifying compounds that modulate bitter taste
|
Agonist activity at human TAS2R13 expressed in HEK293T cells co-expressing Galpha15 assessed as increase in intracellular calcium level by Calcium-3 dye based fluorescence assay
|
Homo sapiens
|
4.9
nM
|
|
Title : Assays for identifying compounds that modulate bitter taste
|
Agonist activity at human TAS2R7 expressed in HEK293T cells co-expressing Galpha15 assessed as increase in intracellular calcium level by Calcium-3 dye based fluorescence assay
|
Homo sapiens
|
4.9
nM
|
|
Title : Assays for identifying compounds that modulate bitter taste
|
Agonist activity at human TAS2R3 expressed in HEK293T cells co-expressing Galpha15 assessed as increase in intracellular calcium level by Calcium-3 dye based fluorescence assay
|
Homo sapiens
|
4.9
nM
|
|
Title : Assays for identifying compounds that modulate bitter taste
|
Agonist activity at human TAS2R43 expressed in HEK293T cells co-expressing Galpha15 assessed as increase in intracellular calcium level by Calcium-3 dye based fluorescence assay
|
Homo sapiens
|
4.9
nM
|
|
Title : Assays for identifying compounds that modulate bitter taste
|
Agonist activity at human TAS2R38 expressed in HEK293T cells co-expressing Galpha15 assessed as increase in intracellular calcium level by Calcium-3 dye based fluorescence assay
|
Homo sapiens
|
4.9
nM
|
|
Title : Assays for identifying compounds that modulate bitter taste
|
Agonist activity at human TAS2R45 expressed in HEK293T cells co-expressing Galpha15 assessed as increase in intracellular calcium level by Calcium-3 dye based fluorescence assay
|
Homo sapiens
|
4.9
nM
|
|
Title : Assays for identifying compounds that modulate bitter taste
|
Agonist activity at human TAS2R46 expressed in HEK293T cells co-expressing Galpha15 assessed as increase in intracellular calcium level by Calcium-3 dye based fluorescence assay
|
Homo sapiens
|
4.9
nM
|
|
Title : Assays for identifying compounds that modulate bitter taste
|
Agonist activity at human TAS2R50 expressed in HEK293T cells co-expressing Galpha15 assessed as increase in intracellular calcium level by Calcium-3 dye based fluorescence assay
|
Homo sapiens
|
4.9
nM
|
|
Title : Assays for identifying compounds that modulate bitter taste
|
Agonist activity at human TAS2R5 expressed in HEK293T cells co-expressing Galpha15 assessed as increase in intracellular calcium level by Calcium-3 dye based fluorescence assay
|
Homo sapiens
|
4.9
nM
|
|
Title : Assays for identifying compounds that modulate bitter taste
|
Agonist activity at human TAS2R44 expressed in HEK293T cells co-expressing Galpha15 assessed as increase in intracellular calcium level by Calcium-3 dye based fluorescence assay
|
Homo sapiens
|
4.9
nM
|
|
Title : Assays for identifying compounds that modulate bitter taste
|
Agonist activity at human TAS2R55 expressed in HEK293T cells co-expressing Galpha15 assessed as increase in intracellular calcium level by Calcium-3 dye based fluorescence assay
|
Homo sapiens
|
4.9
nM
|
|
Title : Assays for identifying compounds that modulate bitter taste
|
Agonist activity at human TAS2R16 expressed in HEK293T cells co-expressing Galpha15 assessed as increase in intracellular calcium level by Calcium-3 dye based fluorescence assay
|
Homo sapiens
|
4.9
nM
|
|
Title : Assays for identifying compounds that modulate bitter taste
|
Agonist activity at human TAS2R14 expressed in HEK293T cells co-expressing Galpha15 assessed as increase in intracellular calcium level by Calcium-3 dye based fluorescence assay
|
Homo sapiens
|
4.9
nM
|
|
Title : Assays for identifying compounds that modulate bitter taste
|
Agonist activity at human TAS2R10 expressed in HEK293T cells co-expressing Galpha15 assessed as increase in intracellular calcium level by Calcium-3 dye based fluorescence assay
|
Homo sapiens
|
4.9
nM
|
|
Title : Assays for identifying compounds that modulate bitter taste
|
Agonist activity at human TAS2R48 expressed in HEK293T cells co-expressing Galpha15 assessed as increase in intracellular calcium level by Calcium-3 dye based fluorescence assay
|
Homo sapiens
|
4.9
nM
|
|
Title : Assays for identifying compounds that modulate bitter taste
|
Agonist activity at human TAS2R41 expressed in HEK293T cells co-expressing Galpha15 assessed as increase in intracellular calcium level by Calcium-3 dye based fluorescence assay
|
Homo sapiens
|
4.9
nM
|
|
Title : Assays for identifying compounds that modulate bitter taste
|
Agonist activity at human TAS2R40 expressed in HEK293T cells co-expressing Galpha15 assessed as increase in intracellular calcium level by Calcium-3 dye based fluorescence assay
|
Homo sapiens
|
4.9
nM
|
|
Title : Assays for identifying compounds that modulate bitter taste
|
Agonist activity at human TAS2R60 expressed in HEK293T cells co-expressing Galpha15 assessed as increase in intracellular calcium level by Calcium-3 dye based fluorescence assay
|
Homo sapiens
|
4.9
nM
|
|
Title : Assays for identifying compounds that modulate bitter taste
|
Agonist activity at human TAS2R49 expressed in HEK293T cells co-expressing Galpha15 assessed as increase in intracellular calcium level by Calcium-3 dye based fluorescence assay
|
Homo sapiens
|
4.9
nM
|
|
Title : Assays for identifying compounds that modulate bitter taste
|
Agonist activity at human TAS2R47 expressed in HEK293T cells co-expressing Galpha15 assessed as increase in intracellular calcium level by Calcium-3 dye based fluorescence assay
|
Homo sapiens
|
4.9
nM
|
|
Title : Assays for identifying compounds that modulate bitter taste
|
Agonist activity at human TAS2R39 expressed in HEK293T cells co-expressing Galpha15 assessed as increase in intracellular calcium level by Calcium-3 dye based fluorescence assay
|
Homo sapiens
|
4.9
nM
|
|
Title : Assays for identifying compounds that modulate bitter taste
|
Agonist activity at human TAS2R9 expressed in HEK293T cells co-expressing Galpha15 assessed as increase in intracellular calcium level by Calcium-3 dye based fluorescence assay
|
Homo sapiens
|
4.9
nM
|
|
Title : Assays for identifying compounds that modulate bitter taste
|
Agonist activity at human TAS2R4 expressed in HEK293T cells co-expressing Galpha15 assessed as increase in intracellular calcium level by Calcium-3 dye based fluorescence assay
|
Homo sapiens
|
4.9
nM
|
|
Title : Assays for identifying compounds that modulate bitter taste
|
Displacement of [3H]DHA from inactive/G protein-uncoupled human beta2-AR expressed in CHO cell membranes by liquid scintillation counting
|
Homo sapiens
|
130.0
nM
|
|
Journal : J Med Chem
Title : Uncoupling the Structure-Activity Relationships of β2 Adrenergic Receptor Ligands from Membrane Binding.
Year : 2016
Volume : 59
Issue : 12
First Page : 5780
Last Page : 5789
Authors : Dickson CJ, Hornak V, Velez-Vega C, McKay DJ, Reilly J, Sandham DA, Shaw D, Fairhurst RA, Charlton SJ, Sykes DA, Pearlstein RA, Duca JS.
Abstract : Ligand binding to membrane proteins may be significantly influenced by the interaction of ligands with the membrane. In particular, the microscopic ligand concentration within the membrane surface solvation layer may exceed that in bulk solvent, resulting in overestimation of the intrinsic protein-ligand binding contribution to the apparent/measured affinity. Using published binding data for a set of small molecules with the β2 adrenergic receptor, we demonstrate that deconvolution of membrane and protein binding contributions allows for improved structure-activity relationship analysis and structure-based drug design. Molecular dynamics simulations of ligand bound membrane protein complexes were used to validate binding poses, allowing analysis of key interactions and binding site solvation to develop structure-activity relationships of β2 ligand binding. The resulting relationships are consistent with intrinsic binding affinity (corrected for membrane interaction). The successful structure-based design of ligands targeting membrane proteins may require an assessment of membrane affinity to uncouple protein binding from membrane interactions.
|
Displacement of [3H]DHA from inactive/G protein-uncoupled human beta2-AR expressed in CHO cell membranes assessed as intrinsic Kd by liquid scintillation counting
|
Homo sapiens
|
740.0
nM
|
|
Journal : J Med Chem
Title : Uncoupling the Structure-Activity Relationships of β2 Adrenergic Receptor Ligands from Membrane Binding.
Year : 2016
Volume : 59
Issue : 12
First Page : 5780
Last Page : 5789
Authors : Dickson CJ, Hornak V, Velez-Vega C, McKay DJ, Reilly J, Sandham DA, Shaw D, Fairhurst RA, Charlton SJ, Sykes DA, Pearlstein RA, Duca JS.
Abstract : Ligand binding to membrane proteins may be significantly influenced by the interaction of ligands with the membrane. In particular, the microscopic ligand concentration within the membrane surface solvation layer may exceed that in bulk solvent, resulting in overestimation of the intrinsic protein-ligand binding contribution to the apparent/measured affinity. Using published binding data for a set of small molecules with the β2 adrenergic receptor, we demonstrate that deconvolution of membrane and protein binding contributions allows for improved structure-activity relationship analysis and structure-based drug design. Molecular dynamics simulations of ligand bound membrane protein complexes were used to validate binding poses, allowing analysis of key interactions and binding site solvation to develop structure-activity relationships of β2 ligand binding. The resulting relationships are consistent with intrinsic binding affinity (corrected for membrane interaction). The successful structure-based design of ligands targeting membrane proteins may require an assessment of membrane affinity to uncouple protein binding from membrane interactions.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
17.95
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.07
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.07
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
|
Agonist activity at human beta1 adrenoreceptor overexpressed in HEK293 cells assessed as cAMP accumulation
|
Homo sapiens
|
1.259
nM
|
|
|
Agonist activity at human beta2 adrenoreceptor overexpressed in HEK293 cells assessed as cAMP accumulation
|
Homo sapiens
|
0.2138
nM
|
|
