|
Binding affinity for human beta-2 adrenergic receptor
|
Homo sapiens
|
1.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Long-chain formoterol analogues: an investigation into the effect of increasing amino-substituent chain length on the beta2-adrenoceptor activity.
Year : 2004
Volume : 14
Issue : 18
First Page : 4705
Last Page : 4710
Authors : Alikhani V, Beer D, Bentley D, Bruce I, Cuenoud BM, Fairhurst RA, Gedeck P, Haberthuer S, Hayden C, Janus D, Jordan L, Lewis C, Smithies K, Wissler E.
Abstract : The synthesis of a series of long-chain formoterol analogues in which the terminal ether residue of the beta-phenethyl-amino-substituent has been extended beyond the methyl ether residue present in the parent compound are described. Evaluation of these analogues as beta(2)-adrenoceptor agonists was used to provide an insight into the factors controlling the magnitude and duration of receptor activation.
|
Concentration required to inhibit electrically induced contraction of superfused guinea-pig trachea was determined
|
Cavia porcellus
|
15.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Long-chain formoterol analogues: an investigation into the effect of increasing amino-substituent chain length on the beta2-adrenoceptor activity.
Year : 2004
Volume : 14
Issue : 18
First Page : 4705
Last Page : 4710
Authors : Alikhani V, Beer D, Bentley D, Bruce I, Cuenoud BM, Fairhurst RA, Gedeck P, Haberthuer S, Hayden C, Janus D, Jordan L, Lewis C, Smithies K, Wissler E.
Abstract : The synthesis of a series of long-chain formoterol analogues in which the terminal ether residue of the beta-phenethyl-amino-substituent has been extended beyond the methyl ether residue present in the parent compound are described. Evaluation of these analogues as beta(2)-adrenoceptor agonists was used to provide an insight into the factors controlling the magnitude and duration of receptor activation.
|
Agonist activity at human recombinant beta-2 adrenoceptor expressed in CHO cells assessed as elevation of cAMP
|
Homo sapiens
|
0.07
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The discovery of long acting beta2-adrenoreceptor agonists.
Year : 2007
Volume : 17
Issue : 14
First Page : 4012
Last Page : 4015
Authors : Brown AD, Bunnage ME, Glossop PA, James K, Jones R, Lane CA, Lewthwaite RA, Mantell S, Perros-Huguet C, Price DA, Trevethick M, Webster R.
Abstract : The design and profile of a series of saligenin containing long acting beta(2)-adrenoreceptor agonists is described. Evaluation of these analogues using a guinea-pig tissue model demonstrates that analogues within this series have significantly longer durations of action than salmeterol and have the potential for a once daily profile in human.
|
Agonist activity at human recombinant adrenergic beta-2 receptor expressed in CHO cells assessed as elevation in cAMP levels
|
Homo sapiens
|
0.07
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The discovery of indole-derived long acting beta2-adrenoceptor agonists for the treatment of asthma and COPD.
Year : 2007
Volume : 17
Issue : 22
First Page : 6188
Last Page : 6191
Authors : Brown AD, Bunnage ME, Glossop PA, Holbrook M, Jones RD, Lane CA, Lewthwaite RA, Mantell S, Perros-Huguet C, Price DA, Webster R.
Abstract : The design and profile of a series of indole containing long acting beta(2)-adrenoceptor agonists is described. Evaluation of these analogues using an in vitro guinea pig trachea tissue model demonstrates that analogues within this series have salmeterol-like duration of action with potential for long duration of action in humans.
|
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
|
794.33
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
|
0.2512
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 beta-1 adrenergic receptor in guinea pig trachea assessed as inhibition of electrical stimulation-induced muscle contraction
|
Cavia porcellus
|
5.012
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.
|
Inhibition of prostaglandin F2alpha-induced contraction in human lung bronchus
|
Homo sapiens
|
5.0
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.
|
Displacement of [125I]cyanopindolol from human recombinant beta2 adrenergic receptor expressed in CHO cells by filtration assay
|
Homo sapiens
|
0.39
nM
|
|
Journal : J. Med. Chem.
Title : The identification of indacaterol as an ultralong-acting inhaled beta2-adrenoceptor agonist.
Year : 2010
Volume : 53
Issue : 9
First Page : 3675
Last Page : 3684
Authors : Baur F, Beattie D, Beer D, Bentley D, Bradley M, Bruce I, Charlton SJ, Cuenoud B, Ernst R, Fairhurst RA, Faller B, Farr D, Keller T, Fozard JR, Fullerton J, Garman S, Hatto J, Hayden C, He H, Howes C, Janus D, Jiang Z, Lewis C, Loeuillet-Ritzler F, Moser H, Reilly J, Steward A, Sykes D, Tedaldi L, Trifilieff A, Tweed M, Watson S, Wissler E, Wyss D.
Abstract : Following a lipophilicity-based hypothesis, an 8-hydroxyquinolinone 2-aminoindan derived series of beta(2)-adrenoceptor agonists have been prepared and evaluated for their potential as inhaled ultralong-acting bronchodilators. Determination of their activities at the human beta(2)-adrenoceptor receptor showed symmetrical substitution of the 2-aminoindan moiety at the 5- and 6-positions delivered the targeted intermediate potency and intrinsic-efficacy profiles relative to a series of clinical reference beta(2)-adrenoceptor agonists. Further assessment with an in vitro superfused electrically stimulated guinea-pig tracheal-strip assay established the onset and duration of action time courses, which could be rationalized by considering the lipophilicity, potency, and intrinsic efficacy of the compounds. From these studies the 5,6-diethylindan analogue indacaterol 1c was shown to possess a unique profile of combining a rapid onset of action with a long duration of action. Further in vivo profiling of 1c supported the long duration of action and a wide therapeutic index following administration to the lung, which led to the compound being selected as a development candidate.
|
Agonist activity at human beta2 adrenergic receptor assessed as increase in cAMP level by whole cell assay
|
Homo sapiens
|
0.32
nM
|
|
Journal : J. Med. Chem.
Title : The identification of indacaterol as an ultralong-acting inhaled beta2-adrenoceptor agonist.
Year : 2010
Volume : 53
Issue : 9
First Page : 3675
Last Page : 3684
Authors : Baur F, Beattie D, Beer D, Bentley D, Bradley M, Bruce I, Charlton SJ, Cuenoud B, Ernst R, Fairhurst RA, Faller B, Farr D, Keller T, Fozard JR, Fullerton J, Garman S, Hatto J, Hayden C, He H, Howes C, Janus D, Jiang Z, Lewis C, Loeuillet-Ritzler F, Moser H, Reilly J, Steward A, Sykes D, Tedaldi L, Trifilieff A, Tweed M, Watson S, Wissler E, Wyss D.
Abstract : Following a lipophilicity-based hypothesis, an 8-hydroxyquinolinone 2-aminoindan derived series of beta(2)-adrenoceptor agonists have been prepared and evaluated for their potential as inhaled ultralong-acting bronchodilators. Determination of their activities at the human beta(2)-adrenoceptor receptor showed symmetrical substitution of the 2-aminoindan moiety at the 5- and 6-positions delivered the targeted intermediate potency and intrinsic-efficacy profiles relative to a series of clinical reference beta(2)-adrenoceptor agonists. Further assessment with an in vitro superfused electrically stimulated guinea-pig tracheal-strip assay established the onset and duration of action time courses, which could be rationalized by considering the lipophilicity, potency, and intrinsic efficacy of the compounds. From these studies the 5,6-diethylindan analogue indacaterol 1c was shown to possess a unique profile of combining a rapid onset of action with a long duration of action. Further in vivo profiling of 1c supported the long duration of action and a wide therapeutic index following administration to the lung, which led to the compound being selected as a development candidate.
|
Agonist activity at beta2 adrenergic receptor in guinea pig tracheal strip assessed as inhibition of electrically-induced bronchocontractile response after 30 mins
|
Cavia porcellus
|
3.5
nM
|
|
Journal : J. Med. Chem.
Title : The identification of indacaterol as an ultralong-acting inhaled beta2-adrenoceptor agonist.
Year : 2010
Volume : 53
Issue : 9
First Page : 3675
Last Page : 3684
Authors : Baur F, Beattie D, Beer D, Bentley D, Bradley M, Bruce I, Charlton SJ, Cuenoud B, Ernst R, Fairhurst RA, Faller B, Farr D, Keller T, Fozard JR, Fullerton J, Garman S, Hatto J, Hayden C, He H, Howes C, Janus D, Jiang Z, Lewis C, Loeuillet-Ritzler F, Moser H, Reilly J, Steward A, Sykes D, Tedaldi L, Trifilieff A, Tweed M, Watson S, Wissler E, Wyss D.
Abstract : Following a lipophilicity-based hypothesis, an 8-hydroxyquinolinone 2-aminoindan derived series of beta(2)-adrenoceptor agonists have been prepared and evaluated for their potential as inhaled ultralong-acting bronchodilators. Determination of their activities at the human beta(2)-adrenoceptor receptor showed symmetrical substitution of the 2-aminoindan moiety at the 5- and 6-positions delivered the targeted intermediate potency and intrinsic-efficacy profiles relative to a series of clinical reference beta(2)-adrenoceptor agonists. Further assessment with an in vitro superfused electrically stimulated guinea-pig tracheal-strip assay established the onset and duration of action time courses, which could be rationalized by considering the lipophilicity, potency, and intrinsic efficacy of the compounds. From these studies the 5,6-diethylindan analogue indacaterol 1c was shown to possess a unique profile of combining a rapid onset of action with a long duration of action. Further in vivo profiling of 1c supported the long duration of action and a wide therapeutic index following administration to the lung, which led to the compound being selected as a development candidate.
|
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
|
0.2512
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
|
794.33
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.
|
Inhibition of CETP in rabbit serum at 10 uM after 1 hr by fluorescent cholesteryl esters transfer assay
|
Oryctolagus cuniculus
|
27.4
%
|
|
Journal : Eur. J. Med. Chem.
Title : Discovery of new cholesteryl ester transfer protein inhibitors via ligand-based pharmacophore modeling and QSAR analysis followed by synthetic exploration.
Year : 2010
Volume : 45
Issue : 4
First Page : 1598
Last Page : 1617
Authors : Abu Khalaf R, Abu Sheikha G, Bustanji Y, Taha MO.
Abstract : Cholesteryl ester transfer protein (CETP) is involved in trafficking lipoprotein particles and neutral lipids between HDL and LDL and therefore is considered a valid target for treating dyslipidemic conditions and complications. Pharmacophore modeling and quantitative structure-activity relationship (QSAR) analysis were combined to explore the structural requirements for potent CETP inhibitors. Two pharmacophores emerged in the optimal QSAR equation (r(2)=0.800, n=96, F=72.1, r(2)(LOO) =0.775, r(2)(PRESS) against 22 external test inhibitors=0.707) suggesting the existence of at least two distinct binding modes accessible to ligands within CETP binding pocket. The successful pharmacophores were complemented with strict shape constraints in an attempt to optimize their receiver-operating characteristic (ROC) curve profiles. The validity of our modeling approach was experimentally established by the identification of several CETP inhibitory leads retrieved via in silico screening of the National Cancer Institute (NCI) list of compounds and an in house built database of drugs and agrochemicals. Two hits illustrated low micromolar IC(50) values: NSC 40331 (IC(50)=6.5 microM) and NSC 89508 (IC(50)=1.9 microM). Active hits were then used to guide synthetic exploration of a new series of CETP inhibitors.
|
Displacement of [3H]CGP12177 from human beta2 adrenoceptor
|
Homo sapiens
|
3.2
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A physical properties based approach for the exploration of a 4-hydroxybenzothiazolone series of beta2-adrenoceptor agonists as inhaled long-acting bronchodilators.
Year : 2010
Volume : 20
Issue : 17
First Page : 5302
Last Page : 5307
Authors : Beattie D, Bradley M, Brearley A, Charlton SJ, Cuenoud BM, Fairhurst RA, Gedeck P, Gosling M, Janus D, Jones D, Lewis C, McCarthy C, Oakman H, Stringer R, Taylor RJ, Tuffnell A.
Abstract : The chiral synthesis of a 4-hydroxybenzothiazolone based series of beta(2)-adrenoceptor agonists is described. Using this methodology a library of N-substituted analogues were prepared for the rapid identification of leads with the potential to be fast onset and long-acting inhaled bronchodilators with improved therapeutic margins. The design of the library to achieve the targeted profile was based upon lipophilicity and metabolism based hypotheses. This approach identified beta-phenethyl, alpha-substituted cyclopentyl and monoterpene N-substituents to be of particular interest for further evaluation, as exemplified by structures 19, 29 and 33, respectively.
|
Displacement of [3H]CGP12177 from human beta-1 adrenoceptor
|
Homo sapiens
|
801.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A physical properties based approach for the exploration of a 4-hydroxybenzothiazolone series of beta2-adrenoceptor agonists as inhaled long-acting bronchodilators.
Year : 2010
Volume : 20
Issue : 17
First Page : 5302
Last Page : 5307
Authors : Beattie D, Bradley M, Brearley A, Charlton SJ, Cuenoud BM, Fairhurst RA, Gedeck P, Gosling M, Janus D, Jones D, Lewis C, McCarthy C, Oakman H, Stringer R, Taylor RJ, Tuffnell A.
Abstract : The chiral synthesis of a 4-hydroxybenzothiazolone based series of beta(2)-adrenoceptor agonists is described. Using this methodology a library of N-substituted analogues were prepared for the rapid identification of leads with the potential to be fast onset and long-acting inhaled bronchodilators with improved therapeutic margins. The design of the library to achieve the targeted profile was based upon lipophilicity and metabolism based hypotheses. This approach identified beta-phenethyl, alpha-substituted cyclopentyl and monoterpene N-substituents to be of particular interest for further evaluation, as exemplified by structures 19, 29 and 33, respectively.
|
Agonist activity at human recombinant beta2 adrenergic receptor expressed in CHO cells assessed as elevation in cAMP level after 1 hr by flashplate method
|
Homo sapiens
|
0.07
nM
|
|
Journal : J. Med. Chem.
Title : Inhalation by design: novel ultra-long-acting β(2)-adrenoreceptor agonists for inhaled once-daily treatment of asthma and chronic obstructive pulmonary disease that utilize a sulfonamide agonist headgroup.
Year : 2010
Volume : 53
Issue : 18
First Page : 6640
Last Page : 6652
Authors : Glossop PA, Lane CA, Price DA, Bunnage ME, Lewthwaite RA, James K, Brown AD, Yeadon M, Perros-Huguet C, Trevethick MA, Clarke NP, Webster R, Jones RM, Burrows JL, Feeder N, Taylor SC, Spence FJ.
Abstract : A novel series of potent and selective sulfonamide derived β(2)-adrenoreceptor agonists are described that exhibit potential as inhaled ultra-long-acting bronchodilators for the treatment of asthma and chronic obstructive pulmonary disease. Analogues from this series mediate very long-lasting smooth muscle relaxation in guinea pig tracheal strips. The sulfonamide agonist headgroup confers high levels of intrinsic crystallinity that could relate to the acidic sulfonamide motif supporting a zwitterionic form in the solid state. Optimization of pharmacokinetic properties was achieved through targeted introduction of a phenolic moiety to support rapid phase II clearance, thereby minimizing systemic exposure following inhalation and reducing systemically mediated adverse events. Compound 38 (PF-610355) is identified as a clinical candidate from this series, with in vivo duration of action studies confirming its potential for once-daily use in humans. Compound 38 is currently in advanced phase II clinical studies.
|
Displacement of [3H]-dihydroalprenolol from human beta2-adrenoceptor expressed in HEK cells after 4 hrs
|
Homo sapiens
|
2.4
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of muscarinic acetylcholine receptor antagonist and beta 2 adrenoceptor agonist (MABA) dual pharmacology molecules.
Year : 2011
Volume : 21
Issue : 5
First Page : 1354
Last Page : 1358
Authors : Hughes AD, Chin KH, Dunham SL, Jasper JR, King KE, Lee TW, Mammen M, Martin J, Steinfeld T.
Abstract : We sought to design dual pharmacology bronchodilators targeting both the M(3) muscarinic acetylcholine and beta-2 adrenergic (β(2)) receptors by applying our multivalent approach to drug discovery. Herein, we describe our initial discovery and the SAR of the first such compounds with matched potencies at both receptors.
|
Agonist activity at human beta2-adrenoceptor expressed in HEK cells assessed as increase of cAMP level after 10 mins by radioimmunoassay
|
Homo sapiens
|
0.33
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of muscarinic acetylcholine receptor antagonist and beta 2 adrenoceptor agonist (MABA) dual pharmacology molecules.
Year : 2011
Volume : 21
Issue : 5
First Page : 1354
Last Page : 1358
Authors : Hughes AD, Chin KH, Dunham SL, Jasper JR, King KE, Lee TW, Mammen M, Martin J, Steinfeld T.
Abstract : We sought to design dual pharmacology bronchodilators targeting both the M(3) muscarinic acetylcholine and beta-2 adrenergic (β(2)) receptors by applying our multivalent approach to drug discovery. Herein, we describe our initial discovery and the SAR of the first such compounds with matched potencies at both receptors.
|
Displacement of [125I]-CYP from human beta2-adrenergic receptor expressed in COS-7 cells by gamma counting
|
Homo sapiens
|
1.5
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Comparative molecular field analysis of fenoterol derivatives: A platform towards highly selective and effective beta(2)-adrenergic receptor agonists.
Year : 2010
Volume : 18
Issue : 2
First Page : 728
Last Page : 736
Authors : Jozwiak K, Woo AY, Tanga MJ, Toll L, Jimenez L, Kozocas JA, Plazinska A, Xiao RP, Wainer IW.
Abstract : To use a previously developed CoMFA model to design a series of new structures of high selectivity and efficacy towards the beta(2)-adrenergic receptor.Out of 21 computationally designed structures 6 compounds were synthesized and characterized for beta(2)-AR binding affinities, subtype selectivities and functional activities.the best compound is (R,R)-4-methoxy-1-naphthylfelnoterol with K(i)beta(2)-AR=0.28microm, K(i)beta(1)-AR/K(i)beta(2)-AR=573, EC(50cAMP)=3.9nm, EC(50cardio)=16nm. The CoMFA model appears to be an effective predictor of the cardiomocyte contractility of the studied compounds which are targeted for use in congestive heart failure.
|
Displacement of [125I]-CYP from human beta2-adrenergic receptor Y308A mutant expressed in COS-7 cells by gamma counting
|
Homo sapiens
|
184.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Comparative molecular field analysis of fenoterol derivatives: A platform towards highly selective and effective beta(2)-adrenergic receptor agonists.
Year : 2010
Volume : 18
Issue : 2
First Page : 728
Last Page : 736
Authors : Jozwiak K, Woo AY, Tanga MJ, Toll L, Jimenez L, Kozocas JA, Plazinska A, Xiao RP, Wainer IW.
Abstract : To use a previously developed CoMFA model to design a series of new structures of high selectivity and efficacy towards the beta(2)-adrenergic receptor.Out of 21 computationally designed structures 6 compounds were synthesized and characterized for beta(2)-AR binding affinities, subtype selectivities and functional activities.the best compound is (R,R)-4-methoxy-1-naphthylfelnoterol with K(i)beta(2)-AR=0.28microm, K(i)beta(1)-AR/K(i)beta(2)-AR=573, EC(50cAMP)=3.9nm, EC(50cardio)=16nm. The CoMFA model appears to be an effective predictor of the cardiomocyte contractility of the studied compounds which are targeted for use in congestive heart failure.
|
Agonist activity at human adrenergic beta2 receptor expressed in H292 cells assessed as intracellular cAMP accumulation after 1 hr
|
Homo sapiens
|
0.7943
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 beta2 receptor expressed in H292 cells assessed as stimulation of cAMP accumulation after 60 mins
|
Homo sapiens
|
0.7943
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design-driven LO: the discovery of new ultra long acting dibasic β2-adrenoceptor agonists.
Year : 2011
Volume : 21
Issue : 15
First Page : 4612
Last Page : 4616
Authors : Connolly S, Alcaraz L, Bailey A, Cadogan E, Christie J, Cook AR, Fisher AJ, Hill S, Humphries A, Ingall AH, Kane Z, Paine S, Pairaudeau G, Stocks MJ, Young A.
Abstract : Starting with the molecular scaffold of the DA(2)/β(2) dual agonist sibenadet (Viozan™), a number of molecular changes were incorporated, which were designed to increase the potency and selectivity of the target molecule, and improve its pharmacokinetics. Through this process a novel, high potency, full β(2)-agonist with high selectivity and long duration capable of being dosed once daily has been discovered.
|
Binding affinity to adrenergic beta1 receptor
|
None
|
501.19
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design-driven LO: the discovery of new ultra long acting dibasic β2-adrenoceptor agonists.
Year : 2011
Volume : 21
Issue : 15
First Page : 4612
Last Page : 4616
Authors : Connolly S, Alcaraz L, Bailey A, Cadogan E, Christie J, Cook AR, Fisher AJ, Hill S, Humphries A, Ingall AH, Kane Z, Paine S, Pairaudeau G, Stocks MJ, Young A.
Abstract : Starting with the molecular scaffold of the DA(2)/β(2) dual agonist sibenadet (Viozan™), a number of molecular changes were incorporated, which were designed to increase the potency and selectivity of the target molecule, and improve its pharmacokinetics. Through this process a novel, high potency, full β(2)-agonist with high selectivity and long duration capable of being dosed once daily has been discovered.
|
Agonist activity at adrenergic beta1 receptor
|
None
|
794.33
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design-driven LO: the discovery of new ultra long acting dibasic β2-adrenoceptor agonists.
Year : 2011
Volume : 21
Issue : 15
First Page : 4612
Last Page : 4616
Authors : Connolly S, Alcaraz L, Bailey A, Cadogan E, Christie J, Cook AR, Fisher AJ, Hill S, Humphries A, Ingall AH, Kane Z, Paine S, Pairaudeau G, Stocks MJ, Young A.
Abstract : Starting with the molecular scaffold of the DA(2)/β(2) dual agonist sibenadet (Viozan™), a number of molecular changes were incorporated, which were designed to increase the potency and selectivity of the target molecule, and improve its pharmacokinetics. Through this process a novel, high potency, full β(2)-agonist with high selectivity and long duration capable of being dosed once daily has been discovered.
|
Agonist activity at adrenergic beta2 receptor in guinea pig trachea assessed as inhibition of electrically-stimulated contraction
|
Cavia porcellus
|
5.012
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
|
794.33
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
|
0.2512
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
|
0.2512
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
|
794.33
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 beta2 adrenergic receptor in guinea pig tracheal strip assessed as inhibition of electrically-induced bronchocontractile response
|
Cavia porcellus
|
5.012
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.
|
Displacement of [3H]dihydroalprenolol from beta2-adrenoceptor after 90 mins by liquid scintillation counting
|
None
|
5.012
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A multivalent approach to the discovery of long-acting β(2)-adrenoceptor agonists for the treatment of asthma and COPD.
Year : 2012
Volume : 22
Issue : 2
First Page : 1213
Last Page : 1218
Authors : Jacobsen JR, Choi SK, Combs J, Fournier EJ, Klein U, Pfeiffer JW, Thomas GR, Yu C, Moran EJ.
Abstract : A multivalent approach was applied to the design of long-acting inhaled β(2)-adrenoceptor agonists. A series of dimeric arylethanolamines based on the short acting β(2)-adrenoceptor agonist albuterol were prepared, varying the nature and length of the linker between the basic nitrogens. None of the C(2)-symmetric dimers demonstrated increased potency, however dimer 5j, derived from 4-phenethylamine, was found to have increased binding potency in vitro relative to the parent monomer. Optimization of this structure led to the identification of 22 (milveterol) which demonstrates high potency in vitro and long duration of action in a guinea pig model of bronchoprotection.
|
Agonist activity at recombinant human beta2-adrenoceptor expressed in whole cells assessed as cAMP accumulation by homogeneous radioimmunoassay
|
Homo sapiens
|
0.3162
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A multivalent approach to the discovery of long-acting β(2)-adrenoceptor agonists for the treatment of asthma and COPD.
Year : 2012
Volume : 22
Issue : 2
First Page : 1213
Last Page : 1218
Authors : Jacobsen JR, Choi SK, Combs J, Fournier EJ, Klein U, Pfeiffer JW, Thomas GR, Yu C, Moran EJ.
Abstract : A multivalent approach was applied to the design of long-acting inhaled β(2)-adrenoceptor agonists. A series of dimeric arylethanolamines based on the short acting β(2)-adrenoceptor agonist albuterol were prepared, varying the nature and length of the linker between the basic nitrogens. None of the C(2)-symmetric dimers demonstrated increased potency, however dimer 5j, derived from 4-phenethylamine, was found to have increased binding potency in vitro relative to the parent monomer. Optimization of this structure led to the identification of 22 (milveterol) which demonstrates high potency in vitro and long duration of action in a guinea pig model of bronchoprotection.
|
Agonist activity at recombinant human beta1-adrenoceptor expressed in whole cells assessed as cAMP accumulation by homogeneous radioimmunoassay
|
Homo sapiens
|
251.19
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A multivalent approach to the discovery of long-acting β(2)-adrenoceptor agonists for the treatment of asthma and COPD.
Year : 2012
Volume : 22
Issue : 2
First Page : 1213
Last Page : 1218
Authors : Jacobsen JR, Choi SK, Combs J, Fournier EJ, Klein U, Pfeiffer JW, Thomas GR, Yu C, Moran EJ.
Abstract : A multivalent approach was applied to the design of long-acting inhaled β(2)-adrenoceptor agonists. A series of dimeric arylethanolamines based on the short acting β(2)-adrenoceptor agonist albuterol were prepared, varying the nature and length of the linker between the basic nitrogens. None of the C(2)-symmetric dimers demonstrated increased potency, however dimer 5j, derived from 4-phenethylamine, was found to have increased binding potency in vitro relative to the parent monomer. Optimization of this structure led to the identification of 22 (milveterol) which demonstrates high potency in vitro and long duration of action in a guinea pig model of bronchoprotection.
|
Agonist activity at beta2-adrenoceptor endogenously expressed in human BEAS-2B cells assessed as cAMP accumulation by homogeneous radioimmunoassay
|
Homo sapiens
|
0.5012
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A multivalent approach to the discovery of long-acting β(2)-adrenoceptor agonists for the treatment of asthma and COPD.
Year : 2012
Volume : 22
Issue : 2
First Page : 1213
Last Page : 1218
Authors : Jacobsen JR, Choi SK, Combs J, Fournier EJ, Klein U, Pfeiffer JW, Thomas GR, Yu C, Moran EJ.
Abstract : A multivalent approach was applied to the design of long-acting inhaled β(2)-adrenoceptor agonists. A series of dimeric arylethanolamines based on the short acting β(2)-adrenoceptor agonist albuterol were prepared, varying the nature and length of the linker between the basic nitrogens. None of the C(2)-symmetric dimers demonstrated increased potency, however dimer 5j, derived from 4-phenethylamine, was found to have increased binding potency in vitro relative to the parent monomer. Optimization of this structure led to the identification of 22 (milveterol) which demonstrates high potency in vitro and long duration of action in a guinea pig model of bronchoprotection.
|
Agonist activity at human beta2 adrenoceptor expressed in H292 cells assessed as increase in cAMP accumulation after 60 mins by spectrophotometry
|
Homo sapiens
|
0.7943
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : From libraries to candidate: the discovery of new ultra long-acting dibasic β₂-adrenoceptor agonists.
Year : 2012
Volume : 22
Issue : 1
First Page : 689
Last Page : 695
Authors : Alcaraz L, Bailey A, Cadogan E, Connolly S, Jewell R, Jordan S, Kindon N, Lister A, Lawson M, Mullen A, Dainty I, Nicholls D, Paine S, Pairaudeau G, Stocks MJ, Thorne P, Young A.
Abstract : Libraries of dibasic compounds designed around the molecular scaffold of the DA(2)/β(2) dual agonist sibenadet (Viozan™) have yielded a number of promising starting points that have been further optimised into novel potent and selective target molecules with required pharmacokinetic properties. From a shortlist, 31 was discovered as a novel, high potency, and highly efficacious β(2)-agonist with high selectivity and a duration of action commensurable with once daily dosing.
|
Binding affinity to beta1 adrenoceptor
|
None
|
501.19
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : From libraries to candidate: the discovery of new ultra long-acting dibasic β₂-adrenoceptor agonists.
Year : 2012
Volume : 22
Issue : 1
First Page : 689
Last Page : 695
Authors : Alcaraz L, Bailey A, Cadogan E, Connolly S, Jewell R, Jordan S, Kindon N, Lister A, Lawson M, Mullen A, Dainty I, Nicholls D, Paine S, Pairaudeau G, Stocks MJ, Thorne P, Young A.
Abstract : Libraries of dibasic compounds designed around the molecular scaffold of the DA(2)/β(2) dual agonist sibenadet (Viozan™) have yielded a number of promising starting points that have been further optimised into novel potent and selective target molecules with required pharmacokinetic properties. From a shortlist, 31 was discovered as a novel, high potency, and highly efficacious β(2)-agonist with high selectivity and a duration of action commensurable with once daily dosing.
|
Agonist activity at human beta1 adrenoceptor transfected in CHO cells assessed as cyclic AMP accumulation after 45 mins by fluorescence polarization assay
|
Homo sapiens
|
794.33
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of a rapidly metabolized, long-acting β(2) adrenergic receptor agonist with a short onset time incorporating a sulfone group suitable for once-daily dosing.
Year : 2014
Volume : 57
Issue : 1
First Page : 159
Last Page : 170
Authors : Procopiou PA, Barrett VJ, Biggadike K, Butchers PR, Craven A, Ford AJ, Guntrip SB, Holmes DS, Hughes SC, Jones AE, Looker BE, Mutch PJ, Ruston M, Needham D, Smith CE.
Abstract : A series of novel, potent, and selective human β2 adrenoceptor agonists incorporating a sulfone moiety on the terminal right-hand-side phenyl ring of (R)-salmeterol is presented. Sulfone 10b had salmeterol-like potency and selectivity profile, long duration of action on guinea pig trachea, and longer than salmeterol duration of action in vivo, suitable for once-daily dosing. It had lower than salmeterol oral absorption in rat, lower bioavailability in rat and dog, and a high turnover in human hepatocytes. It was metabolized in human hepatocytes by hydroxylation, oxidation, cleavage, and conjugation; most of the metabolites would be expected to have reduced or no β2 activity. The 4-biphenylsulfonic acid was identified as a crystalline, non-hygroscopic salt of 10b, suitable for inhaled delivery. Furthermore, it was free of any genetic toxicity issues and was considered as a backup to vilanterol.
|
Agonist activity at human beta2 adrenoceptor transfected in CHO cells assessed as cyclic AMP accumulation after 45 mins by fluorescence polarization assay
|
Homo sapiens
|
0.2512
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of a rapidly metabolized, long-acting β(2) adrenergic receptor agonist with a short onset time incorporating a sulfone group suitable for once-daily dosing.
Year : 2014
Volume : 57
Issue : 1
First Page : 159
Last Page : 170
Authors : Procopiou PA, Barrett VJ, Biggadike K, Butchers PR, Craven A, Ford AJ, Guntrip SB, Holmes DS, Hughes SC, Jones AE, Looker BE, Mutch PJ, Ruston M, Needham D, Smith CE.
Abstract : A series of novel, potent, and selective human β2 adrenoceptor agonists incorporating a sulfone moiety on the terminal right-hand-side phenyl ring of (R)-salmeterol is presented. Sulfone 10b had salmeterol-like potency and selectivity profile, long duration of action on guinea pig trachea, and longer than salmeterol duration of action in vivo, suitable for once-daily dosing. It had lower than salmeterol oral absorption in rat, lower bioavailability in rat and dog, and a high turnover in human hepatocytes. It was metabolized in human hepatocytes by hydroxylation, oxidation, cleavage, and conjugation; most of the metabolites would be expected to have reduced or no β2 activity. The 4-biphenylsulfonic acid was identified as a crystalline, non-hygroscopic salt of 10b, suitable for inhaled delivery. Furthermore, it was free of any genetic toxicity issues and was considered as a backup to vilanterol.
|
Agonist activity at human recombinant beta2 receptor assessed as cAMP accumulation by radioimmunoassay and cell based assay
|
Homo sapiens
|
0.3162
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Multivalent design of long-acting β(2)-adrenoceptor agonists incorporating biarylamines.
Year : 2014
Volume : 24
Issue : 12
First Page : 2625
Last Page : 2630
Authors : Jacobsen JR, Aggen JB, Church TJ, Klein U, Pfeiffer JW, Pulido-Rios TM, Thomas GR, Yu C, Moran EJ.
Abstract : A series of potent β2-adrenoceptor agonists incorporating a biarylamine secondary binding group was identified. The previously reported milveterol (5), identified by a multivalent approach and containing a typical β2-agonist primary binding group linked via a phenethylamine linker to a hydrophilic secondary binding group, served as an initiation point. A more hydrophobic set of secondary binding groups was explored, prepared rapidly from a common intermediate by Buchwald-Hartwig amination. TD-5471 (25), a potent and selective full agonist of the human β2-adrenoceptor, was identified as the most promising agent. It is potent, with slow onset in an in vitro guinea pig trachea model and shows a dose-dependent and long duration of action in an in vivo guinea pig model of bronchoprotection. TD-5471 is structurally differentiated from milveterol and its long duration of action is consistent with a correlation with hydrophobicity observed in other long-acting β2-agonist discovery programs.
|
Displacement of [3H]dihydroalprenolol from beta2 receptor (unknown origin) by liquid scintillation counting and cell based assay
|
Homo sapiens
|
2.512
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Multivalent design of long-acting β(2)-adrenoceptor agonists incorporating biarylamines.
Year : 2014
Volume : 24
Issue : 12
First Page : 2625
Last Page : 2630
Authors : Jacobsen JR, Aggen JB, Church TJ, Klein U, Pfeiffer JW, Pulido-Rios TM, Thomas GR, Yu C, Moran EJ.
Abstract : A series of potent β2-adrenoceptor agonists incorporating a biarylamine secondary binding group was identified. The previously reported milveterol (5), identified by a multivalent approach and containing a typical β2-agonist primary binding group linked via a phenethylamine linker to a hydrophilic secondary binding group, served as an initiation point. A more hydrophobic set of secondary binding groups was explored, prepared rapidly from a common intermediate by Buchwald-Hartwig amination. TD-5471 (25), a potent and selective full agonist of the human β2-adrenoceptor, was identified as the most promising agent. It is potent, with slow onset in an in vitro guinea pig trachea model and shows a dose-dependent and long duration of action in an in vivo guinea pig model of bronchoprotection. TD-5471 is structurally differentiated from milveterol and its long duration of action is consistent with a correlation with hydrophobicity observed in other long-acting β2-agonist discovery programs.
|
Agonist activity at beta2 receptor in guinea pig trachea assessed as slow onset of inhibition of electrically stimulated contraction
|
Cavia porcellus
|
31.62
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Multivalent design of long-acting β(2)-adrenoceptor agonists incorporating biarylamines.
Year : 2014
Volume : 24
Issue : 12
First Page : 2625
Last Page : 2630
Authors : Jacobsen JR, Aggen JB, Church TJ, Klein U, Pfeiffer JW, Pulido-Rios TM, Thomas GR, Yu C, Moran EJ.
Abstract : A series of potent β2-adrenoceptor agonists incorporating a biarylamine secondary binding group was identified. The previously reported milveterol (5), identified by a multivalent approach and containing a typical β2-agonist primary binding group linked via a phenethylamine linker to a hydrophilic secondary binding group, served as an initiation point. A more hydrophobic set of secondary binding groups was explored, prepared rapidly from a common intermediate by Buchwald-Hartwig amination. TD-5471 (25), a potent and selective full agonist of the human β2-adrenoceptor, was identified as the most promising agent. It is potent, with slow onset in an in vitro guinea pig trachea model and shows a dose-dependent and long duration of action in an in vivo guinea pig model of bronchoprotection. TD-5471 is structurally differentiated from milveterol and its long duration of action is consistent with a correlation with hydrophobicity observed in other long-acting β2-agonist discovery programs.
|
Agonist activity at human recombinant beta1 receptor assessed as cAMP accumulation by radioimmunoassay and cell based assay
|
Homo sapiens
|
251.19
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Multivalent design of long-acting β(2)-adrenoceptor agonists incorporating biarylamines.
Year : 2014
Volume : 24
Issue : 12
First Page : 2625
Last Page : 2630
Authors : Jacobsen JR, Aggen JB, Church TJ, Klein U, Pfeiffer JW, Pulido-Rios TM, Thomas GR, Yu C, Moran EJ.
Abstract : A series of potent β2-adrenoceptor agonists incorporating a biarylamine secondary binding group was identified. The previously reported milveterol (5), identified by a multivalent approach and containing a typical β2-agonist primary binding group linked via a phenethylamine linker to a hydrophilic secondary binding group, served as an initiation point. A more hydrophobic set of secondary binding groups was explored, prepared rapidly from a common intermediate by Buchwald-Hartwig amination. TD-5471 (25), a potent and selective full agonist of the human β2-adrenoceptor, was identified as the most promising agent. It is potent, with slow onset in an in vitro guinea pig trachea model and shows a dose-dependent and long duration of action in an in vivo guinea pig model of bronchoprotection. TD-5471 is structurally differentiated from milveterol and its long duration of action is consistent with a correlation with hydrophobicity observed in other long-acting β2-agonist discovery programs.
|
Agonist activity at human beta2 receptor in BEAS-2B cells assessed as cAMP accumulation by radioimmunoassay
|
Homo sapiens
|
0.5012
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Multivalent design of long-acting β(2)-adrenoceptor agonists incorporating biarylamines.
Year : 2014
Volume : 24
Issue : 12
First Page : 2625
Last Page : 2630
Authors : Jacobsen JR, Aggen JB, Church TJ, Klein U, Pfeiffer JW, Pulido-Rios TM, Thomas GR, Yu C, Moran EJ.
Abstract : A series of potent β2-adrenoceptor agonists incorporating a biarylamine secondary binding group was identified. The previously reported milveterol (5), identified by a multivalent approach and containing a typical β2-agonist primary binding group linked via a phenethylamine linker to a hydrophilic secondary binding group, served as an initiation point. A more hydrophobic set of secondary binding groups was explored, prepared rapidly from a common intermediate by Buchwald-Hartwig amination. TD-5471 (25), a potent and selective full agonist of the human β2-adrenoceptor, was identified as the most promising agent. It is potent, with slow onset in an in vitro guinea pig trachea model and shows a dose-dependent and long duration of action in an in vivo guinea pig model of bronchoprotection. TD-5471 is structurally differentiated from milveterol and its long duration of action is consistent with a correlation with hydrophobicity observed in other long-acting β2-agonist discovery programs.
|
Displacement of [125I]iodo-(+/-)-cyanopindolol from human adrenergic beta2 receptor expressed in CHO cells after 3 hrs by radio-ligand binding assay
|
Homo sapiens
|
3.2
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The identification of 7-[(R)-2-((1S,2S)-2-benzyloxycyclopentylamino)-1-hydroxyethyl]-4-hydroxybenzothiazolone as an inhaled long-acting β2-adrenoceptor agonist.
Year : 2014
Volume : 24
Issue : 17
First Page : 4341
Last Page : 4347
Authors : Arnold N, Beattie D, Bradley M, Brearley A, Brown L, Charlton SJ, Fairhurst RA, Farr D, Fozard J, Fullerton J, Gosling M, Hatto J, Janus D, Jones D, Jordan L, Lewis C, Maas J, McCarthy C, Mercer M, Oakman H, Press N, Profit R, Schuerch F, Sykes D, Taylor RJ, Trifilieff A, Tuffnell A.
Abstract : The optimisation of two series of 4-hydroxybenzothiazolone derived β2-adrenoceptor agonists, bearing α-substituted cyclopentyl and β-phenethyl amino-substituents, as inhaled long-acting bronchodilators is described. Analogues were selected for synthesis using a lipophilicity based hypothesis to achieve the targeted rapid onset of action in combination with a long duration of action. The profiling of the two series led to identification of the α-substituted cyclopentyl analogue 2 as the optimal compound with a comparable profile to the inhaled once-daily long-acting β2-adrenoceptor agonist indacaterol. On the basis of these data 2 was promoted as the backup development candidate to indacaterol from the Novartis LABA project.
|
Displacement of [125I]iodo-(+/-)-cyanopindolol from human adrenergic beta1 receptor expressed in CHO cells after 3 hrs by radio-ligand binding assay
|
Homo sapiens
|
784.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The identification of 7-[(R)-2-((1S,2S)-2-benzyloxycyclopentylamino)-1-hydroxyethyl]-4-hydroxybenzothiazolone as an inhaled long-acting β2-adrenoceptor agonist.
Year : 2014
Volume : 24
Issue : 17
First Page : 4341
Last Page : 4347
Authors : Arnold N, Beattie D, Bradley M, Brearley A, Brown L, Charlton SJ, Fairhurst RA, Farr D, Fozard J, Fullerton J, Gosling M, Hatto J, Janus D, Jones D, Jordan L, Lewis C, Maas J, McCarthy C, Mercer M, Oakman H, Press N, Profit R, Schuerch F, Sykes D, Taylor RJ, Trifilieff A, Tuffnell A.
Abstract : The optimisation of two series of 4-hydroxybenzothiazolone derived β2-adrenoceptor agonists, bearing α-substituted cyclopentyl and β-phenethyl amino-substituents, as inhaled long-acting bronchodilators is described. Analogues were selected for synthesis using a lipophilicity based hypothesis to achieve the targeted rapid onset of action in combination with a long duration of action. The profiling of the two series led to identification of the α-substituted cyclopentyl analogue 2 as the optimal compound with a comparable profile to the inhaled once-daily long-acting β2-adrenoceptor agonist indacaterol. On the basis of these data 2 was promoted as the backup development candidate to indacaterol from the Novartis LABA project.
|
Agonist activity at adrenergic beta2 receptor in electrically-stimulated Dunkin-Hartley guinea pig tracheal strip assessed as inhibition of contraction
|
Cavia porcellus
|
3.5
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The identification of 7-[(R)-2-((1S,2S)-2-benzyloxycyclopentylamino)-1-hydroxyethyl]-4-hydroxybenzothiazolone as an inhaled long-acting β2-adrenoceptor agonist.
Year : 2014
Volume : 24
Issue : 17
First Page : 4341
Last Page : 4347
Authors : Arnold N, Beattie D, Bradley M, Brearley A, Brown L, Charlton SJ, Fairhurst RA, Farr D, Fozard J, Fullerton J, Gosling M, Hatto J, Janus D, Jones D, Jordan L, Lewis C, Maas J, McCarthy C, Mercer M, Oakman H, Press N, Profit R, Schuerch F, Sykes D, Taylor RJ, Trifilieff A, Tuffnell A.
Abstract : The optimisation of two series of 4-hydroxybenzothiazolone derived β2-adrenoceptor agonists, bearing α-substituted cyclopentyl and β-phenethyl amino-substituents, as inhaled long-acting bronchodilators is described. Analogues were selected for synthesis using a lipophilicity based hypothesis to achieve the targeted rapid onset of action in combination with a long duration of action. The profiling of the two series led to identification of the α-substituted cyclopentyl analogue 2 as the optimal compound with a comparable profile to the inhaled once-daily long-acting β2-adrenoceptor agonist indacaterol. On the basis of these data 2 was promoted as the backup development candidate to indacaterol from the Novartis LABA project.
|
Displacement of [3H]dihydroalprenolol from human beta2 adrenergic receptor expressing cell membrane by competition binding assay
|
Homo sapiens
|
2.512
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of TD-4306, a long-acting β2-agonist for the treatment of asthma and COPD.
Year : 2014
Volume : 24
Issue : 13
First Page : 2871
Last Page : 2876
Authors : McKinnell RM, Klein U, Linsell MS, Moran EJ, Nodwell MB, Pfeiffer JW, Thomas GR, Yu C, Jacobsen JR.
Abstract : A multivalent approach focused on amine-based secondary binding groups was applied to the discovery of long-acting inhaled β2-agonists. Addition of amine moieties to the neutral secondary binding group of an existing β2-agonist series was found to provide improved in vivo efficacy, but also led to the formation of biologically active aldehyde metabolites which were viewed as a risk for the development of these compounds. Structural simplification of the scaffold and blocking the site of metabolism to prevent aldehyde formation afforded a potent series of dibasic β2-agonists with improved duration of action relative to their monobasic analogs. Additional optimization led to the discovery of 29 (TD-4306), a potent and selective β2-agonist with potential for once-daily dosing.
|
Agonist activity at human beta1 adrenergic receptor expressed in cells by cAMP accumulation assay
|
Homo sapiens
|
251.19
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of TD-4306, a long-acting β2-agonist for the treatment of asthma and COPD.
Year : 2014
Volume : 24
Issue : 13
First Page : 2871
Last Page : 2876
Authors : McKinnell RM, Klein U, Linsell MS, Moran EJ, Nodwell MB, Pfeiffer JW, Thomas GR, Yu C, Jacobsen JR.
Abstract : A multivalent approach focused on amine-based secondary binding groups was applied to the discovery of long-acting inhaled β2-agonists. Addition of amine moieties to the neutral secondary binding group of an existing β2-agonist series was found to provide improved in vivo efficacy, but also led to the formation of biologically active aldehyde metabolites which were viewed as a risk for the development of these compounds. Structural simplification of the scaffold and blocking the site of metabolism to prevent aldehyde formation afforded a potent series of dibasic β2-agonists with improved duration of action relative to their monobasic analogs. Additional optimization led to the discovery of 29 (TD-4306), a potent and selective β2-agonist with potential for once-daily dosing.
|
Agonist activity at human beta2 adrenergic receptor expressed in cells by cAMP accumulation assay
|
Homo sapiens
|
0.3162
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of TD-4306, a long-acting β2-agonist for the treatment of asthma and COPD.
Year : 2014
Volume : 24
Issue : 13
First Page : 2871
Last Page : 2876
Authors : McKinnell RM, Klein U, Linsell MS, Moran EJ, Nodwell MB, Pfeiffer JW, Thomas GR, Yu C, Jacobsen JR.
Abstract : A multivalent approach focused on amine-based secondary binding groups was applied to the discovery of long-acting inhaled β2-agonists. Addition of amine moieties to the neutral secondary binding group of an existing β2-agonist series was found to provide improved in vivo efficacy, but also led to the formation of biologically active aldehyde metabolites which were viewed as a risk for the development of these compounds. Structural simplification of the scaffold and blocking the site of metabolism to prevent aldehyde formation afforded a potent series of dibasic β2-agonists with improved duration of action relative to their monobasic analogs. Additional optimization led to the discovery of 29 (TD-4306), a potent and selective β2-agonist with potential for once-daily dosing.
|
Agonist activity at human beta2 adrenergic receptor in human BEAS-2B cells by cAMP accumulation assay
|
Homo sapiens
|
0.5012
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of TD-4306, a long-acting β2-agonist for the treatment of asthma and COPD.
Year : 2014
Volume : 24
Issue : 13
First Page : 2871
Last Page : 2876
Authors : McKinnell RM, Klein U, Linsell MS, Moran EJ, Nodwell MB, Pfeiffer JW, Thomas GR, Yu C, Jacobsen JR.
Abstract : A multivalent approach focused on amine-based secondary binding groups was applied to the discovery of long-acting inhaled β2-agonists. Addition of amine moieties to the neutral secondary binding group of an existing β2-agonist series was found to provide improved in vivo efficacy, but also led to the formation of biologically active aldehyde metabolites which were viewed as a risk for the development of these compounds. Structural simplification of the scaffold and blocking the site of metabolism to prevent aldehyde formation afforded a potent series of dibasic β2-agonists with improved duration of action relative to their monobasic analogs. Additional optimization led to the discovery of 29 (TD-4306), a potent and selective β2-agonist with potential for once-daily dosing.
|
Activity at beta2 adrenoceptor/muscarinic M3 receptor in guinea pig trachea assessed as inhibition of electric fileld-stimulated contraction
|
Cavia porcellus
|
6.9
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Molecular hybridization yields triazole bronchodilators for the treatment of COPD.
Year : 2015
Volume : 25
Issue : 22
First Page : 5121
Last Page : 5126
Authors : Jones LH, Burrows J, Feeder N, Glossop P, James K, Jones RM, Kenyon AS, Patel S, Roberts DF, Selby MD, Strang RS, Stuart EF, Trevethick MA, Watson J, Wright KN, Clarke N.
Abstract : A 1,2,4-triazole motif was employed as a bioisostere for the ester commonly used in muscarinic antagonists, and subsequent integrative conjugation to a β2 agonist quinolinone furnished a new class of bifunctional MABAs for the treatment of COPD. Medicinal chemistry optimization using the principles of 'inhalation by design' furnished a clinical candidate with desirable pharmacological, pharmacokinetic and biopharmaceutical properties.
|
Agonist activity at beta2 adrenoceptor in guinea pig trachea assessed as inhibition of histamine-induced contraction
|
Cavia porcellus
|
2.7
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Molecular hybridization yields triazole bronchodilators for the treatment of COPD.
Year : 2015
Volume : 25
Issue : 22
First Page : 5121
Last Page : 5126
Authors : Jones LH, Burrows J, Feeder N, Glossop P, James K, Jones RM, Kenyon AS, Patel S, Roberts DF, Selby MD, Strang RS, Stuart EF, Trevethick MA, Watson J, Wright KN, Clarke N.
Abstract : A 1,2,4-triazole motif was employed as a bioisostere for the ester commonly used in muscarinic antagonists, and subsequent integrative conjugation to a β2 agonist quinolinone furnished a new class of bifunctional MABAs for the treatment of COPD. Medicinal chemistry optimization using the principles of 'inhalation by design' furnished a clinical candidate with desirable pharmacological, pharmacokinetic and biopharmaceutical properties.
|
Displacement of [3H]CGP12177 from human beta2 receptor expressed in CHO cells
|
Homo sapiens
|
0.18
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.
|
Antibacterial activity against Staphylococcus aureus MRSA ATCC 43300 (CO-ADD:GP_020); MIC in CAMBH media, using NBS plates, by OD(600)
|
Staphylococcus aureus subsp. aureus
|
15.16
%
|
|
|
Antibacterial activity against Escherichia coli ATCC 25922 (CO-ADD:GN_001); MIC in CAMBH media using NBS plates, by OD(600)
|
Escherichia coli
|
8.33
%
|
|
|
Antibacterial activity against Klebsiella pneumoniae MDR ATCC 70063 (CO-ADD:GN_003); MIC in CAMBH media using NBS plates, by OD(600)
|
Klebsiella pneumoniae
|
16.35
%
|
|
|
Antibacterial activity against Pseudomonas aeruginosa ATCC 27853 (CO-ADD:GN_042); MIC in CAMBH media using NBS plates, by OD(600)
|
Pseudomonas aeruginosa
|
18.07
%
|
|
|
Antibacterial activity against Acinetobacter baumannii ATCC 19606 (CO-ADD:GN_034); MIC in CAMBH media using NBS plates, by OD600
|
Acinetobacter baumannii
|
31.88
%
|
|
|
Antifungal activity against Candida albicans ATCC 90028 (CO-ADD:FG_001); MIC in YNB media using NBS plates, by OD630
|
Candida albicans
|
5.42
%
|
|
|
Antifungal activity against Cryptococcus neoformans H99 ATCC 208821 (CO-ADD:FG_002); MIC in YNB media using NBS plates, by Resazurin OD(600-570)
|
Cryptococcus neoformans
|
-8.37
%
|
|
|
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
|
0.07762
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.
|
Displacement of [3H]-CGP-12177 from murine beta1-adrenergic receptor expressed in HEK293T cells after 60 mins by radioligand competition binding assay
|
Mus musculus
|
550.0
nM
|
|
Journal : J Med Chem
Title : Hybridization of β-Adrenergic Agonists and Antagonists Confers G Protein Bias.
Year : 2019
Volume : 62
Issue : 10
First Page : 5111
Last Page : 5131
Authors : Stanek M, Picard LP, Schmidt MF, Kaindl JM, Hübner H, Bouvier M, Weikert D, Gmeiner P.
Abstract : Starting from the β-adrenoceptor agonist isoprenaline and beta-blocker carvedilol, we designed and synthesized three different chemotypes of agonist/antagonist hybrids. Investigations of ligand-mediated receptor activation using bioluminescence resonance energy transfer biosensors revealed a predominant effect of the aromatic head group on the intrinsic activity of our ligands, as ligands with a carvedilol head group were devoid of agonistic activity. Ligands composed of a catechol head group and an antagonist-like oxypropylene spacer possess significant intrinsic activity for the activation of Gα<sub>s</sub>, while they only show weak or even no β-arrestin-2 recruitment at both β<sub>1</sub>- and β<sub>2</sub>-AR. Molecular dynamics simulations suggest that the difference in G protein efficacy and β-arrestin recruitment of the hybrid ( S)-22, the full agonist epinephrine, and the β<sub>2</sub>-selective, G protein-biased partial agonist salmeterol depends on specific hydrogen bonding between Ser<sup>5.46</sup> and Asn<sup>6.55</sup>, and the aromatic head group of the ligands.
|
Displacement of [3H]-CGP-12177 from human beta2-adrenergic receptor expressed in CHO cells after 60 mins by radioligand competition binding assay
|
Homo sapiens
|
0.25
nM
|
|
Journal : J Med Chem
Title : Hybridization of β-Adrenergic Agonists and Antagonists Confers G Protein Bias.
Year : 2019
Volume : 62
Issue : 10
First Page : 5111
Last Page : 5131
Authors : Stanek M, Picard LP, Schmidt MF, Kaindl JM, Hübner H, Bouvier M, Weikert D, Gmeiner P.
Abstract : Starting from the β-adrenoceptor agonist isoprenaline and beta-blocker carvedilol, we designed and synthesized three different chemotypes of agonist/antagonist hybrids. Investigations of ligand-mediated receptor activation using bioluminescence resonance energy transfer biosensors revealed a predominant effect of the aromatic head group on the intrinsic activity of our ligands, as ligands with a carvedilol head group were devoid of agonistic activity. Ligands composed of a catechol head group and an antagonist-like oxypropylene spacer possess significant intrinsic activity for the activation of Gα<sub>s</sub>, while they only show weak or even no β-arrestin-2 recruitment at both β<sub>1</sub>- and β<sub>2</sub>-AR. Molecular dynamics simulations suggest that the difference in G protein efficacy and β-arrestin recruitment of the hybrid ( S)-22, the full agonist epinephrine, and the β<sub>2</sub>-selective, G protein-biased partial agonist salmeterol depends on specific hydrogen bonding between Ser<sup>5.46</sup> and Asn<sup>6.55</sup>, and the aromatic head group of the ligands.
|
Agonist activity at beta1-adrenergic receptor (unknown origin) expressed in HEK293T cells harboring GFP/Rluc2-tagged beta-arrestin2 assessed as increase in beta-arrestin2 recruitment incubated for 5 mins in presence of GRK5 and coelenterazine 400a by BRET assay
|
Homo sapiens
|
199.53
nM
|
|
Journal : J Med Chem
Title : Hybridization of β-Adrenergic Agonists and Antagonists Confers G Protein Bias.
Year : 2019
Volume : 62
Issue : 10
First Page : 5111
Last Page : 5131
Authors : Stanek M, Picard LP, Schmidt MF, Kaindl JM, Hübner H, Bouvier M, Weikert D, Gmeiner P.
Abstract : Starting from the β-adrenoceptor agonist isoprenaline and beta-blocker carvedilol, we designed and synthesized three different chemotypes of agonist/antagonist hybrids. Investigations of ligand-mediated receptor activation using bioluminescence resonance energy transfer biosensors revealed a predominant effect of the aromatic head group on the intrinsic activity of our ligands, as ligands with a carvedilol head group were devoid of agonistic activity. Ligands composed of a catechol head group and an antagonist-like oxypropylene spacer possess significant intrinsic activity for the activation of Gα<sub>s</sub>, while they only show weak or even no β-arrestin-2 recruitment at both β<sub>1</sub>- and β<sub>2</sub>-AR. Molecular dynamics simulations suggest that the difference in G protein efficacy and β-arrestin recruitment of the hybrid ( S)-22, the full agonist epinephrine, and the β<sub>2</sub>-selective, G protein-biased partial agonist salmeterol depends on specific hydrogen bonding between Ser<sup>5.46</sup> and Asn<sup>6.55</sup>, and the aromatic head group of the ligands.
|
Agonist activity at beta2-adrenergic receptor (unknown origin) expressed in HEK293T cells harboring Rluc2-117-GalphaS/GFP10-Ggamma/Gbeta1 assessed as activation of GalphaS incubated for 5 mins in presence of coelenterazine 400a by BRET assay
|
Homo sapiens
|
0.7943
nM
|
|
Journal : J Med Chem
Title : Hybridization of β-Adrenergic Agonists and Antagonists Confers G Protein Bias.
Year : 2019
Volume : 62
Issue : 10
First Page : 5111
Last Page : 5131
Authors : Stanek M, Picard LP, Schmidt MF, Kaindl JM, Hübner H, Bouvier M, Weikert D, Gmeiner P.
Abstract : Starting from the β-adrenoceptor agonist isoprenaline and beta-blocker carvedilol, we designed and synthesized three different chemotypes of agonist/antagonist hybrids. Investigations of ligand-mediated receptor activation using bioluminescence resonance energy transfer biosensors revealed a predominant effect of the aromatic head group on the intrinsic activity of our ligands, as ligands with a carvedilol head group were devoid of agonistic activity. Ligands composed of a catechol head group and an antagonist-like oxypropylene spacer possess significant intrinsic activity for the activation of Gα<sub>s</sub>, while they only show weak or even no β-arrestin-2 recruitment at both β<sub>1</sub>- and β<sub>2</sub>-AR. Molecular dynamics simulations suggest that the difference in G protein efficacy and β-arrestin recruitment of the hybrid ( S)-22, the full agonist epinephrine, and the β<sub>2</sub>-selective, G protein-biased partial agonist salmeterol depends on specific hydrogen bonding between Ser<sup>5.46</sup> and Asn<sup>6.55</sup>, and the aromatic head group of the ligands.
|
Agonist activity at beta2-adrenergic receptor (unknown origin) expressed in HEK293T cells harboring GFP/Rluc2-tagged beta-arrestin2 assessed as increase in beta-arrestin2 recruitment incubated for 5 mins in presence of GSK2 and coelenterazine 400a by BRET assay
|
Homo sapiens
|
0.1259
nM
|
|
Journal : J Med Chem
Title : Hybridization of β-Adrenergic Agonists and Antagonists Confers G Protein Bias.
Year : 2019
Volume : 62
Issue : 10
First Page : 5111
Last Page : 5131
Authors : Stanek M, Picard LP, Schmidt MF, Kaindl JM, Hübner H, Bouvier M, Weikert D, Gmeiner P.
Abstract : Starting from the β-adrenoceptor agonist isoprenaline and beta-blocker carvedilol, we designed and synthesized three different chemotypes of agonist/antagonist hybrids. Investigations of ligand-mediated receptor activation using bioluminescence resonance energy transfer biosensors revealed a predominant effect of the aromatic head group on the intrinsic activity of our ligands, as ligands with a carvedilol head group were devoid of agonistic activity. Ligands composed of a catechol head group and an antagonist-like oxypropylene spacer possess significant intrinsic activity for the activation of Gα<sub>s</sub>, while they only show weak or even no β-arrestin-2 recruitment at both β<sub>1</sub>- and β<sub>2</sub>-AR. Molecular dynamics simulations suggest that the difference in G protein efficacy and β-arrestin recruitment of the hybrid ( S)-22, the full agonist epinephrine, and the β<sub>2</sub>-selective, G protein-biased partial agonist salmeterol depends on specific hydrogen bonding between Ser<sup>5.46</sup> and Asn<sup>6.55</sup>, and the aromatic head group of the ligands.
|
Agonist activity at beta2-adrenergic receptor (unknown origin) expressed in HEK293T cells harboring GFP/Rluc2-tagged beta-arrestin2 assessed as increase in beta-arrestin2 recruitment incubated for 5 mins in presence of GSK5 and coelenterazine 400a by BRET assay
|
Homo sapiens
|
0.07943
nM
|
|
Journal : J Med Chem
Title : Hybridization of β-Adrenergic Agonists and Antagonists Confers G Protein Bias.
Year : 2019
Volume : 62
Issue : 10
First Page : 5111
Last Page : 5131
Authors : Stanek M, Picard LP, Schmidt MF, Kaindl JM, Hübner H, Bouvier M, Weikert D, Gmeiner P.
Abstract : Starting from the β-adrenoceptor agonist isoprenaline and beta-blocker carvedilol, we designed and synthesized three different chemotypes of agonist/antagonist hybrids. Investigations of ligand-mediated receptor activation using bioluminescence resonance energy transfer biosensors revealed a predominant effect of the aromatic head group on the intrinsic activity of our ligands, as ligands with a carvedilol head group were devoid of agonistic activity. Ligands composed of a catechol head group and an antagonist-like oxypropylene spacer possess significant intrinsic activity for the activation of Gα<sub>s</sub>, while they only show weak or even no β-arrestin-2 recruitment at both β<sub>1</sub>- and β<sub>2</sub>-AR. Molecular dynamics simulations suggest that the difference in G protein efficacy and β-arrestin recruitment of the hybrid ( S)-22, the full agonist epinephrine, and the β<sub>2</sub>-selective, G protein-biased partial agonist salmeterol depends on specific hydrogen bonding between Ser<sup>5.46</sup> and Asn<sup>6.55</sup>, and the aromatic head group of the ligands.
|
Antiviral activity against DENV2 infected in human Huh7 cells by qRT-PCR analysis
|
Dengue virus 2
|
670.0
nM
|
|
Journal : Eur J Med Chem
Title : Recent update on anti-dengue drug discovery.
Year : 2019
Volume : 176
First Page : 431
Last Page : 455
Authors : Dighe SN, Ekwudu O, Dua K, Chellappan DK, Katavic PL, Collet TA.
Abstract : Dengue is the most important arthropod-borne viral disease of humans, with more than half of the global population living in at-risk areas. Despite the negative impact on public health, there are no antiviral therapies available, and the only licensed vaccine, Dengvaxia<sup>®</sup>, has been contraindicated in children below nine years of age. In an effort to combat dengue, several small molecules have entered into human clinical trials. Here, we review anti-DENV molecules and their drug targets that have been published within the past five years (2014-2018). Further, we discuss their probable mechanisms of action and describe a role for classes of clinically approved drugs and also an unclassified class of anti-DENV agents. This review aims to enhance our understanding of novel agents and their cognate targets in furthering innovations in the use of small molecules for dengue drug therapies.
|
Displacement of [3H]DHA from inactive/G protein-uncoupled human beta2-AR expressed in CHO cell membranes by liquid scintillation counting
|
Homo sapiens
|
0.3
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
|
13.05
%
|
|
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
|
-0.25
%
|
|
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
|
-0.25
%
|
|
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 beta2 adrenoreceptor overexpressed in human HEK293 cells assessed as cAMP accumulation incubated for 60 mins by HTRF assay
|
Homo sapiens
|
0.04467
nM
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis and biological evaluation of 8-(2-amino-1-hydroxyethyl)-6-hydroxy-1,4-benzoxazine-3(4H)-one derivatives as potent β<sub>2</sub>-adrenoceptor agonists.
Year : 2020
Volume : 28
Issue : 1
First Page : 115178
Last Page : 115178
Authors : Yi C, Xing G, Wang S, Li X, Liu Y, Li J, Lin B, Woo AY, Zhang Y, Pan L, Cheng M.
Abstract : A series of β<sub>2</sub>-adrenoceptor agonists with an 8-(2-amino-1-hydroxyethyl)-6-hydroxy-1,4-benzoxazine-3(4H)-one moiety is presented. The stimulatory effects of the compounds on human β<sub>2</sub>-adrenoceptor and β<sub>1</sub>-adrenoceptor were characterized by a cell-based assay. Their smooth muscle relaxant activities were tested on isolated guinea pig trachea. Most of the compounds were found to be potent and selective agonists of the β<sub>2</sub>-adrenoceptor. One of the compounds, (R)-18c, possessed a strong β<sub>2</sub>-adrenoceptor agonistic effect with an EC<sub>50</sub> value of 24 pM. It produced a full and potent airway smooth muscle relaxant effect same as olodaterol. Its onset of action was 3.5 min and its duration of action was more than 12 h in an in vitro guinea pig trachea model of bronchodilation. These results suggest that (R)-18c is a potential candidate for long-acting β<sub>2</sub>-AR agonists.
|
Agonist activity at human beta1 adrenoreceptor overexpressed in human HEK293 cells assessed as cAMP accumulation incubated for 60 mins by HTRF assay
|
Homo sapiens
|
316.23
nM
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis and biological evaluation of 8-(2-amino-1-hydroxyethyl)-6-hydroxy-1,4-benzoxazine-3(4H)-one derivatives as potent β<sub>2</sub>-adrenoceptor agonists.
Year : 2020
Volume : 28
Issue : 1
First Page : 115178
Last Page : 115178
Authors : Yi C, Xing G, Wang S, Li X, Liu Y, Li J, Lin B, Woo AY, Zhang Y, Pan L, Cheng M.
Abstract : A series of β<sub>2</sub>-adrenoceptor agonists with an 8-(2-amino-1-hydroxyethyl)-6-hydroxy-1,4-benzoxazine-3(4H)-one moiety is presented. The stimulatory effects of the compounds on human β<sub>2</sub>-adrenoceptor and β<sub>1</sub>-adrenoceptor were characterized by a cell-based assay. Their smooth muscle relaxant activities were tested on isolated guinea pig trachea. Most of the compounds were found to be potent and selective agonists of the β<sub>2</sub>-adrenoceptor. One of the compounds, (R)-18c, possessed a strong β<sub>2</sub>-adrenoceptor agonistic effect with an EC<sub>50</sub> value of 24 pM. It produced a full and potent airway smooth muscle relaxant effect same as olodaterol. Its onset of action was 3.5 min and its duration of action was more than 12 h in an in vitro guinea pig trachea model of bronchodilation. These results suggest that (R)-18c is a potential candidate for long-acting β<sub>2</sub>-AR agonists.
|
Agonist activity at human beta1 adrenoceptor expressed in CHO cells assessed as increase in intracellular cAMP level incubated for 1 hr by alphascreen technology
|
Homo sapiens
|
67.0
nM
|
|
|
Agonist activity at human beta2 adrenoceptor expressed in CHO cells assessed as increase in intracellular cAMP level incubated for 1 hr by alphascreen technology
|
Homo sapiens
|
0.71
nM
|
|
|
Agonist activity at human beta1 adrenoreceptor overexpressed in HEK293 cells assessed as cAMP accumulation
|
Homo sapiens
|
371.54
nM
|
|
|
Agonist activity at human beta2 adrenoreceptor overexpressed in HEK293 cells assessed as cAMP accumulation
|
Homo sapiens
|
0.1349
nM
|
|
