|
Dissociation constant for binding to isolated membranes from clonal cell line
|
None
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : New developments in Ca2+ channel antagonists.
Year : 1983
Volume : 26
Issue : 6
First Page : 775
Last Page : 785
Authors : Janis RA, Triggle DJ.
Abstract : Toward the beginning of this Perspective we posed a number of questions to be answered concerning the Ca2+ channel antagonists. Biochemical, chemical, clinical, pharmacological, and physiological studies collectively support the conclusion that this important group of molecules does function in specific fashion to inhibit Ca2+ channel function. Major questions of mechanisms and sites of action remain, however, to be resolved. The recent radioligand binding assay supports the conclusion, drawn earlier from the chemical and pharmacological heterogeneity of these agents, that there exists multiple sites and mechanisms of action for the Ca2+ channel antagonists. This is a satisfying conclusion, since, although it makes high demands on future experimentation designed to delineate these sites and mechanisms, it indicates the very real possibility for the development of tissue-selective Ca2+ channel antagonists. Elsewhere in this review we have already addressed the question of tissue selectivity as observed for existing compounds. In our opinion, the structural and pharmacological clues available should bring us closer to the goal of second- and third-generation Ca2+ antagonists with defined tissue selectivity.
|
Dissociation constant for high affinity binding sites in intact cultured cardiac cells
|
None
|
0.26
nM
|
|
Journal : J. Med. Chem.
Title : New developments in Ca2+ channel antagonists.
Year : 1983
Volume : 26
Issue : 6
First Page : 775
Last Page : 785
Authors : Janis RA, Triggle DJ.
Abstract : Toward the beginning of this Perspective we posed a number of questions to be answered concerning the Ca2+ channel antagonists. Biochemical, chemical, clinical, pharmacological, and physiological studies collectively support the conclusion that this important group of molecules does function in specific fashion to inhibit Ca2+ channel function. Major questions of mechanisms and sites of action remain, however, to be resolved. The recent radioligand binding assay supports the conclusion, drawn earlier from the chemical and pharmacological heterogeneity of these agents, that there exists multiple sites and mechanisms of action for the Ca2+ channel antagonists. This is a satisfying conclusion, since, although it makes high demands on future experimentation designed to delineate these sites and mechanisms, it indicates the very real possibility for the development of tissue-selective Ca2+ channel antagonists. Elsewhere in this review we have already addressed the question of tissue selectivity as observed for existing compounds. In our opinion, the structural and pharmacological clues available should bring us closer to the goal of second- and third-generation Ca2+ antagonists with defined tissue selectivity.
|
Dissociation constant for low affinity binding sites in intact cultured cardiac cells
|
None
|
16.0
nM
|
|
Journal : J. Med. Chem.
Title : New developments in Ca2+ channel antagonists.
Year : 1983
Volume : 26
Issue : 6
First Page : 775
Last Page : 785
Authors : Janis RA, Triggle DJ.
Abstract : Toward the beginning of this Perspective we posed a number of questions to be answered concerning the Ca2+ channel antagonists. Biochemical, chemical, clinical, pharmacological, and physiological studies collectively support the conclusion that this important group of molecules does function in specific fashion to inhibit Ca2+ channel function. Major questions of mechanisms and sites of action remain, however, to be resolved. The recent radioligand binding assay supports the conclusion, drawn earlier from the chemical and pharmacological heterogeneity of these agents, that there exists multiple sites and mechanisms of action for the Ca2+ channel antagonists. This is a satisfying conclusion, since, although it makes high demands on future experimentation designed to delineate these sites and mechanisms, it indicates the very real possibility for the development of tissue-selective Ca2+ channel antagonists. Elsewhere in this review we have already addressed the question of tissue selectivity as observed for existing compounds. In our opinion, the structural and pharmacological clues available should bring us closer to the goal of second- and third-generation Ca2+ antagonists with defined tissue selectivity.
|
Inhibition of [3H]nitrendipine binding to L-type calcium channel of guinea pig ileal longitudinal smooth muscle
|
Cavia porcellus
|
0.15
nM
|
|
Journal : J. Med. Chem.
Title : Dimeric 1,4-dihydropyridines as calcium channel antagonists.
Year : 1988
Volume : 31
Issue : 8
First Page : 1489
Last Page : 1492
Authors : Joslyn AF, Luchowski E, Triggle DJ.
Abstract : A series of 1,n-alkanediylbis(1,4-dihydropyridines) (n = 2, 4, 6, 8, 10, 12) bridged at C3 of 2,6-dimethyl-3-carboxy-5-carbethoxy-4-(3-nitrophenyl)-1,4-dihydropyridin e were synthesized and evaluated in a radioligand binding assay, [3H]nitrendipine in intestinal smooth muscle, as Ca2+ channel ligands. Binding activity was comparable to that of nitrendipine itself but independent of chain length, suggesting the lack of a major binding contribution by the second 1,4-dihydropyridine group. Analogues lacking the second 1,4-dihydropyridine nucleus or possessing an inactive function (4-nitrophenyl) were no less active, confirming that this series of ligands likely does not bridge adjacent 1,4-dihydropyridine receptors of the Ca2+ channel.
|
Inhibition of [3H]nitrendipine binding to L-type calcium channel in guinea pig ventricular myocardium membranes
|
Cavia porcellus
|
0.26
nM
|
|
Journal : J. Med. Chem.
Title : Dihydropyrimidine calcium channel blockers: 2-heterosubstituted 4-aryl-1,4-dihydro-6-methyl-5-pyrimidinecarboxylic acid esters as potent mimics of dihydropyridines.
Year : 1990
Volume : 33
Issue : 5
First Page : 1510
Last Page : 1515
Authors : Atwal KS, Rovnyak GC, Schwartz J, Moreland S, Hedberg A, Gougoutas JZ, Malley MF, Floyd DM.
Abstract : 2-Heterosubstituted-4-aryl-1,4-dihydro-6-methyl-5-pyrimidinecar box ylic acid esters 8, which lack the potential CS symmetry of dihydropyridine calcium channel blockers, were prepared and evaluated for biological activity. Biological assays using potassium-depolarized rabbit aorta and radioligand binding techniques showed that some of these compounds are potent mimics of dihydropyridine calcium channel blockers. The combination of a branched ester (e.g. isopropyl, sec-butyl) and an alkylthio group (e.g. SMe) was found to be optimal for biological activity. When compared directly with similarly substituted 2-heteroalkyldihydropyridines 9, dihydropyrimidines 8 were found to be 30-fold less active. The solid-state structure of dihydropyrimidine analogue 8g shows that these compounds can adopt a molecular conformation which is similar to the reported conformation of dihydropyridine calcium channel blockers.
|
In vitro vasorelaxant activity (calcium channel blocking activity) was determined with potassium-depolarized rabbit thoracic aorta
|
None
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : Dihydropyrimidine calcium channel blockers. 2. 3-substituted-4-aryl-1,4-dihydro-6-methyl-5-pyrimidinecarboxylic acid esters as potent mimics of dihydropyridines.
Year : 1990
Volume : 33
Issue : 9
First Page : 2629
Last Page : 2635
Authors : Atwal KS, Rovnyak GC, Kimball SD, Floyd DM, Moreland S, Swanson BN, Gougoutas JZ, Schwartz J, Smillie KM, Malley MF.
Abstract : To enhance the intrinsic potency of dihydropyrimidine calcium channel blockers, we have modified the structure of previously described 2-heteroalkyl-1,4-dihydropyrimidines 2 to 3-substituted 1,4-dihydropyrimidines 3. Structure-activity studies using potassium-depolarized rabbit aorta show that ortho, meta-disubstituted aryl derivatives are more potent than either ortho- or meta-monosubstituted compounds. While vasorelaxant activity was critically dependent on the size of the C5 ester group, isopropyl ester being the best, a variety of substituents (carbamate, acyl, sulfonyl, alkyl) were tolerated at N3. Our results show dihydropyrimidines 3 are significantly more potent than corresponding 2-heteroalkyl-1,4-dihydropyrimidines 2 and only slightly less potent than similarly substituted 2-heteroalkyl-1,4-dihydropyridines 4 and 5. Whereas dihydropyridine enantiomers usually show 10-15-fold difference in activity, the enantiomers of dihydropyrimidine 3j show more than a 1000-fold difference in activity. These results strengthen the requirement of an enamino ester for binding to the dihydropyridine receptor and indicate a nonspecific role for the N3-substituent.
|
Inhibition of [3H]nitrendipine binding to L-type calcium channel dihydropyridine site of porcine cardiac sarcolemma membrane vesicles
|
Sus scrofa
|
0.25
nM
|
|
Journal : J. Med. Chem.
Title : Diethyl 3,6-dihydro-2,4-dimethyl-2,6-methano-1,3-benzothiazocine-5,11- dicarboxylates as calcium entry antagonists: new conformationally restrained analogues of Hantzsch 1,4-dihydropyridines related to nitrendipine as probes for receptor-site conformation.
Year : 1987
Volume : 30
Issue : 4
First Page : 690
Last Page : 695
Authors : Baldwin JJ, Claremon DA, Lumma PK, McClure DE, Rosenthal SA, Winquist RJ, Faison EP, Kaczorowski GJ, Trumble MJ, Smith GM.
Abstract : The pharmacological activity of rigid analogues of 1,4-dihydropyridine calcium entry antagonists 9-16 is demonstrated by dose-dependent inhibition of the calcium contraction in depolarized rat aortic strips and by a [3H]nitrendipine binding assay in using cardiac sarcolemmal membranes. From the results, a model is proposed as the receptor-bound conformation of the dihydropyridine calcium entry antagonists.
|
Compound was tested for percent of fraction inhibition by anti-P-450 NF.
|
None
|
83.0
%
|
|
Journal : J. Med. Chem.
Title : Oxidation of 4-aryl- and 4-alkyl-substituted 2,6-dimethyl-3,5-bis(alkoxycarbonyl)-1,4-dihydropyridines by human liver microsomes and immunochemical evidence for the involvement of a form of cytochrome P-450.
Year : 1986
Volume : 29
Issue : 9
First Page : 1596
Last Page : 1603
Authors : Böcker RH, Guengerich FP.
Abstract : 4-Substituted 2,6-dimethyl-3,5-bis(alkoxycarbonyl)-1,4-dihydropyridines are important because of their roles as calcium channel blockers. The mixed-function oxidation of 14 4-aryl- and four 4-alkyl-substituted derivatives by human liver microsomes was examined. The major product of enzymatic oxidation of all the 4-aryl compounds was the pyridine derivative containing the 4-aryl group. The 4-alkyl compounds, in contrast, formed a pyridine derivative in which a hydrogen atom was present at the 4-position and the alkyl group was lost; these compounds also inactivated cytochrome P-450 and caused the loss of nifedipine oxidase activity after enzymatic oxidation. All of these reactions were extensively inhibited by an antibody raised to purified human liver nifedipine oxidase cytochrome P-450 (P-450NF), indicating a major role for this enzyme in the oxidation of these compounds. Oxidation of the 4-alkyl compounds led not only to the loss of P-450NF but also to decreases in catalytic activities of cytochrome P-450 isozymes catalyzing other reactions (phenacetin O-deethylation and hexobarbital 3'-hydroxylation). The results indicate that P-450NF (or closely related enzyme forms) is responsible for the oxidation of these nifedipine-related compounds in human liver microsomes and that metabolism is highly dependent upon 4-substitution; with alkyl substituents, radicals are postulated to leave P-450NF to attack other proteins.
|
The compound was tested for inhibition of calcium influx into neuronal (NG108-15) cells
|
Mus musculus
|
16.0
nM
|
|
Journal : J. Med. Chem.
Title : Aminoalkynyldithianes. A new class of calcium channel blockers.
Year : 1991
Volume : 34
Issue : 5
First Page : 1585
Last Page : 1593
Authors : Adams TC, Dupont AC, Carter JP, Kachur JF, Guzewska ME, Rzeszotarski WJ, Farmer SG, Noronha-Blob L, Kaiser C.
Abstract : Several dithiane derivatives, prepared as intermediates for compounds structurally related to the therapeutically useful antimuscarinic agent oxybutynin, were effective inhibitors of calcium ion induced contraction of guinea pig ileal strips and of KCl-induced calcium entry into neuronal cells. Although the first member of this series, 2-[5-(diethylamino)-3-pentynyl]-1,3-dithiane (2a), was only marginally effective, its condensation product with diphenyl ketone, i.e. 2-[5-(diethylamino)-3-pentynyl]-2-(a,a-diphenyl-a- hydroxymethyl)-1,3-dithiane (3a), demonstrated weak, but significant, calcium channel antagonist activity. As part of a structure-activity relationship (SAR) study, various structural analogues of 2a and 3a were prepared and examined for calcium antagonist properties. In addition to these structural types, ring bridged (tricyclic) congeners of 3, i.e. 4, related bicyclic compounds 5, dehydroxylated derivatives 6, some homologous 2-[[[(N,N-disubstituted-amino)methyl]2- phenyl-1,3-dithianes (7), and a series of 2-[6-[N,N-disubstituted-amino)methyl]-1-hydroxy-1-phenyl- 4-hexynyl]-1,3-dithianes (8) were prepared and studied for calcium channel blocking activity. In general, greatest potency was noted in the tricyclic series 4; however, a definitive SAR could not be established. A structural similarity between several potent calcium antagonists having the structures 7c, 8b, and 8d and the well-known calcium channel blockers verapamil and tiapamil suggests these compounds may act at the same site. Compounds in the other classes (2-6) failed to show clearly defined SAR and their potency differed markedly in two tests for calcium channel antagonist activity. These results may indicate that the dithiane derivatives 2-6 produce their effects in a manner differing from that of the calcium channel antagonists diltiazem, verapamil, and nitrendepine.
|
Ability to block depolarization induced 45Ca uptake into pheochromocytoma PC12 cells
|
Rattus norvegicus
|
10.0
nM
|
|
Journal : J. Med. Chem.
Title : New developments in Ca2+ channel antagonists.
Year : 1983
Volume : 26
Issue : 6
First Page : 775
Last Page : 785
Authors : Janis RA, Triggle DJ.
Abstract : Toward the beginning of this Perspective we posed a number of questions to be answered concerning the Ca2+ channel antagonists. Biochemical, chemical, clinical, pharmacological, and physiological studies collectively support the conclusion that this important group of molecules does function in specific fashion to inhibit Ca2+ channel function. Major questions of mechanisms and sites of action remain, however, to be resolved. The recent radioligand binding assay supports the conclusion, drawn earlier from the chemical and pharmacological heterogeneity of these agents, that there exists multiple sites and mechanisms of action for the Ca2+ channel antagonists. This is a satisfying conclusion, since, although it makes high demands on future experimentation designed to delineate these sites and mechanisms, it indicates the very real possibility for the development of tissue-selective Ca2+ channel antagonists. Elsewhere in this review we have already addressed the question of tissue selectivity as observed for existing compounds. In our opinion, the structural and pharmacological clues available should bring us closer to the goal of second- and third-generation Ca2+ antagonists with defined tissue selectivity.
|
Tested in vitro for platelet activating factor receptor antagonist activity by inhibiting PAF-induced ATP release in rabbit platelets
|
Oryctolagus cuniculus
|
0.0
%
|
|
Journal : J. Med. Chem.
Title : 4-Alkyl-1,4-dihydropyridines derivatives as specific PAF-acether antagonists.
Year : 1990
Volume : 33
Issue : 12
First Page : 3205
Last Page : 3210
Authors : Sunkel CE, de Casa-Juana MF, Santos L, Gómez MM, Villarroya M, González-Morales MA, Priego JG, Ortega MP.
Abstract : A new series of 4-alkyl-1,4-dihydropyridines (1,4-DHP) were synthesized and evaluated for their ability to inhibit washed rabbit platelet aggregation induced by PAF-acether (1-O-hexadecyl/octadecyl-2-O-acetyl-sn-glycero-3-phosphorylcholine) and to reverse PAF-induced hypotension in anesthetized rats. Additionally, compounds were evaluated for their ability to inhibit the binding of radiolabeled PAF to its receptor on rabbit platelets. Among these compounds, 6I and 6L were the most potent and specific antagonists. At concentrations up to 100 microM, neither compound 6I nor compound 6L caused platelet aggregation nor did they inhibit platelet aggregation induced by collagen or adenosine diphosphate. Compound 6L did not show in vitro calcium channel blocker activity measured on vascular smooth muscle preparations of rabbit aorta and on [3H]nitrendipine binding assays. The compound did not show any cardiovascular effects in anesthetized rat at iv doses up to 1000 micrograms/kg, and the Ki value was 568.62 nmol. These results indicate that compound 6L is a potent and specific PAF antagonist with 1,4-dihydropyridine structure but devoid of a significant cardiovascular activity related to calcium-antagonist properties.
|
Tested in vitro for platelet activating factor receptor antagonist activity by inhibiting PAF-induced platelet aggregation from rabbit
|
Oryctolagus cuniculus
|
0.0
%
|
|
Journal : J. Med. Chem.
Title : 4-Alkyl-1,4-dihydropyridines derivatives as specific PAF-acether antagonists.
Year : 1990
Volume : 33
Issue : 12
First Page : 3205
Last Page : 3210
Authors : Sunkel CE, de Casa-Juana MF, Santos L, Gómez MM, Villarroya M, González-Morales MA, Priego JG, Ortega MP.
Abstract : A new series of 4-alkyl-1,4-dihydropyridines (1,4-DHP) were synthesized and evaluated for their ability to inhibit washed rabbit platelet aggregation induced by PAF-acether (1-O-hexadecyl/octadecyl-2-O-acetyl-sn-glycero-3-phosphorylcholine) and to reverse PAF-induced hypotension in anesthetized rats. Additionally, compounds were evaluated for their ability to inhibit the binding of radiolabeled PAF to its receptor on rabbit platelets. Among these compounds, 6I and 6L were the most potent and specific antagonists. At concentrations up to 100 microM, neither compound 6I nor compound 6L caused platelet aggregation nor did they inhibit platelet aggregation induced by collagen or adenosine diphosphate. Compound 6L did not show in vitro calcium channel blocker activity measured on vascular smooth muscle preparations of rabbit aorta and on [3H]nitrendipine binding assays. The compound did not show any cardiovascular effects in anesthetized rat at iv doses up to 1000 micrograms/kg, and the Ki value was 568.62 nmol. These results indicate that compound 6L is a potent and specific PAF antagonist with 1,4-dihydropyridine structure but devoid of a significant cardiovascular activity related to calcium-antagonist properties.
|
Vasorelaxant potency in isolated potassium (K(+)-depolarized rabbit thoracic aorta.
|
Oryctolagus cuniculus
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : Dihydropyrimidine calcium channel blockers: 2-heterosubstituted 4-aryl-1,4-dihydro-6-methyl-5-pyrimidinecarboxylic acid esters as potent mimics of dihydropyridines.
Year : 1990
Volume : 33
Issue : 5
First Page : 1510
Last Page : 1515
Authors : Atwal KS, Rovnyak GC, Schwartz J, Moreland S, Hedberg A, Gougoutas JZ, Malley MF, Floyd DM.
Abstract : 2-Heterosubstituted-4-aryl-1,4-dihydro-6-methyl-5-pyrimidinecar box ylic acid esters 8, which lack the potential CS symmetry of dihydropyridine calcium channel blockers, were prepared and evaluated for biological activity. Biological assays using potassium-depolarized rabbit aorta and radioligand binding techniques showed that some of these compounds are potent mimics of dihydropyridine calcium channel blockers. The combination of a branched ester (e.g. isopropyl, sec-butyl) and an alkylthio group (e.g. SMe) was found to be optimal for biological activity. When compared directly with similarly substituted 2-heteroalkyldihydropyridines 9, dihydropyrimidines 8 were found to be 30-fold less active. The solid-state structure of dihydropyrimidine analogue 8g shows that these compounds can adopt a molecular conformation which is similar to the reported conformation of dihydropyridine calcium channel blockers.
|
Effective concentration for negative inotropic effect
|
Rattus norvegicus
|
28.0
nM
|
|
Journal : J. Med. Chem.
Title : New developments in Ca2+ channel antagonists.
Year : 1983
Volume : 26
Issue : 6
First Page : 775
Last Page : 785
Authors : Janis RA, Triggle DJ.
Abstract : Toward the beginning of this Perspective we posed a number of questions to be answered concerning the Ca2+ channel antagonists. Biochemical, chemical, clinical, pharmacological, and physiological studies collectively support the conclusion that this important group of molecules does function in specific fashion to inhibit Ca2+ channel function. Major questions of mechanisms and sites of action remain, however, to be resolved. The recent radioligand binding assay supports the conclusion, drawn earlier from the chemical and pharmacological heterogeneity of these agents, that there exists multiple sites and mechanisms of action for the Ca2+ channel antagonists. This is a satisfying conclusion, since, although it makes high demands on future experimentation designed to delineate these sites and mechanisms, it indicates the very real possibility for the development of tissue-selective Ca2+ channel antagonists. Elsewhere in this review we have already addressed the question of tissue selectivity as observed for existing compounds. In our opinion, the structural and pharmacological clues available should bring us closer to the goal of second- and third-generation Ca2+ antagonists with defined tissue selectivity.
|
Dose-dependent inhibition of calcium contraction in depolarized rat aortic strips
|
Rattus norvegicus
|
3.1
nM
|
|
Journal : J. Med. Chem.
Title : Diethyl 3,6-dihydro-2,4-dimethyl-2,6-methano-1,3-benzothiazocine-5,11- dicarboxylates as calcium entry antagonists: new conformationally restrained analogues of Hantzsch 1,4-dihydropyridines related to nitrendipine as probes for receptor-site conformation.
Year : 1987
Volume : 30
Issue : 4
First Page : 690
Last Page : 695
Authors : Baldwin JJ, Claremon DA, Lumma PK, McClure DE, Rosenthal SA, Winquist RJ, Faison EP, Kaczorowski GJ, Trumble MJ, Smith GM.
Abstract : The pharmacological activity of rigid analogues of 1,4-dihydropyridine calcium entry antagonists 9-16 is demonstrated by dose-dependent inhibition of the calcium contraction in depolarized rat aortic strips and by a [3H]nitrendipine binding assay in using cardiac sarcolemmal membranes. From the results, a model is proposed as the receptor-bound conformation of the dihydropyridine calcium entry antagonists.
|
Inhibition of binding of Batrachotoxinin [3H]BTX-B to high affinity sites on voltage dependent sodium channels in a vesicular preparation from guinea pig cerebral cortex at 10 uM
|
Cavia porcellus
|
23.1
%
|
|
Journal : J. Med. Chem.
Title : [3H]Batrachotoxinin A 20 alpha-benzoate binding to voltage-sensitive sodium channels: a rapid and quantitative assay for local anesthetic activity in a variety of drugs.
Year : 1985
Volume : 28
Issue : 3
First Page : 381
Last Page : 388
Authors : McNeal ET, Lewandowski GA, Daly JW, Creveling CR.
Abstract : [3H]Batrachotoxinin A benzoate ( [3H]BTX-B) binds with high affinity to sites on voltage-dependent sodium channels in a vesicular preparation from guinea pig cerebral cortex. In this preparation, local anesthetics competitively antagonize the binding of [3H]BTX-B. The potencies of some 40 classical local anesthetics and a variety of catecholamine, histamine, serotonin, adenosine, GABA, glycine, acetylcholine, and calcium antagonists, tranquilizers, antidepressants, barbiturates, anticonvulsants, steroids, vasodilators, antiinflammatories, anticoagulants, analgesics, and other agents have been determined. An excellent correlation with the known local anesthetic activity of many of these agents indicate that antagonism of binding of [3H]BTX-B binding provides a rapid, quantitative, and facile method for the screening and investigation of local anesthetic activity.
|
Antagonist activity at rat Cav1.3 expressed in HEK293 cells assessed as inhibition of voltage pulse-induced calcium current at 100 nM by FLIPR calcium 4 assay
|
Rattus norvegicus
|
34.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Antagonism of 4-substituted 1,4-dihydropyridine-3,5-dicarboxylates toward voltage-dependent L-type Ca2+ channels Ca V 1.3 and Ca V 1.2.
Year : 2010
Volume : 18
Issue : 9
First Page : 3147
Last Page : 3158
Authors : Chang CC, Cao S, Kang S, Kai L, Tian X, Pandey P, Dunne SF, Luan CH, Surmeier DJ, Silverman RB.
Abstract : L-type Ca(2+) channels in mammalian brain neurons have either a Ca(V)1.2 or Ca(V)1.3 pore-forming subunit. Recently, it was shown that Ca(V)1.3 Ca(2+) channels underlie autonomous pacemaking in adult dopaminergic neurons in the substantia nigra pars compacta, and this reliance renders them sensitive to toxins used to create animal models of Parkinson's disease. Antagonism of these channels with the dihydropyridine antihypertensive drug isradipine diminishes the reliance on Ca(2+) and the sensitivity of these neurons to toxins, pointing to a potential neuroprotective strategy. However, for neuroprotection without an antihypertensive side effect, selective Ca(V)1.3 channel antagonists are required. In an attempt to identify potent and selective antagonists of Ca(V)1.3 channels, 124 dihydropyridines (4-substituted-1,4-dihydropyridine-3,5-dicarboxylic diesters) were synthesized. The antagonism of heterologously expressed Ca(V)1.2 and Ca(V)1.3 channels was then tested using electrophysiological approaches and the FLIPR Calcium 4 assay. Despite the large diversity in substitution on the dihydropyridine scaffold, the most Ca(V)1.3 selectivity was only about twofold. These results support a highly similar dihydropyridine binding site at both Ca(V)1.2 and Ca(V)1.3 channels and suggests that other classes of compounds need to be identified for Ca(V)1.3 selectivity.
|
Antagonist activity at rabbit Cav1.2 expressed in HEK293 cells assessed as inhibition of voltage pulse-induced calcium current at 100 nM by FLIPR calcium 4 assay
|
Oryctolagus cuniculus
|
62.0
%
|
|
Journal : Bioorg. Med. Chem.
Title : Antagonism of 4-substituted 1,4-dihydropyridine-3,5-dicarboxylates toward voltage-dependent L-type Ca2+ channels Ca V 1.3 and Ca V 1.2.
Year : 2010
Volume : 18
Issue : 9
First Page : 3147
Last Page : 3158
Authors : Chang CC, Cao S, Kang S, Kai L, Tian X, Pandey P, Dunne SF, Luan CH, Surmeier DJ, Silverman RB.
Abstract : L-type Ca(2+) channels in mammalian brain neurons have either a Ca(V)1.2 or Ca(V)1.3 pore-forming subunit. Recently, it was shown that Ca(V)1.3 Ca(2+) channels underlie autonomous pacemaking in adult dopaminergic neurons in the substantia nigra pars compacta, and this reliance renders them sensitive to toxins used to create animal models of Parkinson's disease. Antagonism of these channels with the dihydropyridine antihypertensive drug isradipine diminishes the reliance on Ca(2+) and the sensitivity of these neurons to toxins, pointing to a potential neuroprotective strategy. However, for neuroprotection without an antihypertensive side effect, selective Ca(V)1.3 channel antagonists are required. In an attempt to identify potent and selective antagonists of Ca(V)1.3 channels, 124 dihydropyridines (4-substituted-1,4-dihydropyridine-3,5-dicarboxylic diesters) were synthesized. The antagonism of heterologously expressed Ca(V)1.2 and Ca(V)1.3 channels was then tested using electrophysiological approaches and the FLIPR Calcium 4 assay. Despite the large diversity in substitution on the dihydropyridine scaffold, the most Ca(V)1.3 selectivity was only about twofold. These results support a highly similar dihydropyridine binding site at both Ca(V)1.2 and Ca(V)1.3 channels and suggests that other classes of compounds need to be identified for Ca(V)1.3 selectivity.
|
Vasorelaxant activity in Wistar rat endothelium-denuded thoracic aortic ring assessed as inhibition of noradrenaline-induced contraction treated after noradrenaline challenge measured after 60 mins
|
Rattus norvegicus
|
30.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis, vasorelaxant activity and antihypertensive effect of benzo[d]imidazole derivatives.
Year : 2010
Volume : 18
Issue : 11
First Page : 3985
Last Page : 3991
Authors : Navarrete-Vázquez G, Hidalgo-Figueroa S, Torres-Piedra M, Vergara-Galicia J, Rivera-Leyva JC, Estrada-Soto S, Estrada-Soto S, León-Rivera I, Aguilar-Guardarrama B, Rios-Gómez Y, Villalobos-Molina R, Ibarra-Barajas M.
Abstract : A series of 1H-benzo[d]imidazole analogues of Pimobendan, substituted at position 5 with either -CF(3) or -NO(2), were synthesized using a short synthetic route. All the nitro derivatives were potent, and exhibited a concentration- and partial endothelium-dependent vasorelaxant effects, with EC(50)s <5microM. 2-Methoxy-4-[5-nitro-1H-benzo[d]imidazol-2-yl]phenol (compound 13) was the most potent derivative of the series, showing an EC(50) value of 1.81microM and E(max) of 91.7% for ex vivo relaxant response in intact aortic rings, resulting in a 2.5-fold higher activity compared to Pimobendan. The closely related 5-CF(3) analogue (compound 8), was 19 times less potent than 13. The antihypertensive activity of compound 13 was evaluated at doses of 25, 50 and 100mgkg(-1), using spontaneously hypertensive rats (SHR), showing a statistically significant dose-dependent effect.
|
Inhibition of rat L-type Ca2+ channel dihydropyridine site
|
Rattus norvegicus
|
1.3
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery of {1-[4-(2-{hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}-1H-benzimidazol-1-yl)piperidin-1-yl]cyclooctyl}methanol, systemically potent novel non-peptide agonist of nociceptin/orphanin FQ receptor as analgesic for the treatment of neuropathic pain: design, synthesis, and structure-activity relationships.
Year : 2010
Volume : 18
Issue : 21
First Page : 7675
Last Page : 7699
Authors : Hayashi S, Nakata E, Morita A, Mizuno K, Yamamura K, Kato A, Ohashi K.
Abstract : Neuropathic pain is a serious chronic disorder caused by lesion or dysfunction in the nervous systems. Endogenous nociceptin/orphanin FQ (N/OFQ) peptide and N/OFQ peptide (NOP) receptor [or opioid-receptor-like-1 (ORL1) receptor] are located in the central and peripheral nervous systems, the immune systems, and peripheral organs, and have a crucial role in the pain sensory system. Indeed, peripheral or intrathecal N/OFQ has displayed antinociceptive activities in neuropathic pain models, and inhibitory effects on pain-related neurotransmitter releases and on synaptic transmissions of C- and Aδ-fibers. In this study, design, synthesis, and structure-activity relationships of peripheral/spinal cord-targeting non-peptide NOP receptor agonist were investigated for the treatment of neuropathic pain, which resulted in the discovery of highly selective and potent novel NOP receptor full agonist {1-[4-(2-{hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}-1H-benzimidazol-1-yl)piperidin-1-yl]cyclooctyl}methanol 1 (HPCOM) as systemically (subcutaneously) potent new-class analgesic. Thus, 1 demonstrates dose-dependent inhibitory effect against mechanical allodynia in chronic constriction injury-induced neuropathic pain model rats, robust metabolic stability and little hERG potassium ion channel binding affinity, with its unique and potentially safe profiles and mechanisms, which were distinctive from those of N/OFQ in terms of site-differential effects.
|
DRUGMATRIX: Calcium Channel Type L, Benzothiazepine radioligand binding (ligand: [3H] Diltiazem)
|
Rattus norvegicus
|
1.565
nM
|
|
DRUGMATRIX: Calcium Channel Type L, Benzothiazepine radioligand binding (ligand: [3H] Diltiazem)
|
Rattus norvegicus
|
1.391
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: Calcium Channel Type L, Dihydropyridine radioligand binding (ligand: [3H] Nitrendipine)
|
Rattus norvegicus
|
0.383
nM
|
|
DRUGMATRIX: Calcium Channel Type L, Dihydropyridine radioligand binding (ligand: [3H] Nitrendipine)
|
Rattus norvegicus
|
0.246
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
DRUGMATRIX: CYP450, 2C9 enzyme inhibition (substrate: 3-Cyano-7-ethoxycoumarin)
|
None
|
300.0
nM
|
|
Title : DrugMatrix in vitro pharmacology data
Authors : Scott S. Auerbach, DrugMatrix¨ and ToxFX¨ Coordinator National Toxicology Program
Abstract : The DrugMatrix Pharmacology data is a subset of the data freely available from the National Toxicology Program. For more details see:https://ntp.niehs.nih.gov/drugmatrix/index.html
|
Inhibition of human voltage-dependent L-type calcium channel subunit alpha1C/alpha2delta/beta2a expressed in C1-6-37-3 cells assessed as inhibition of K+-induced calcium influx incubated for 30 mins prior to K+-induction by Fluo-4-AM based FLIPR assay
|
Homo sapiens
|
3.0
nM
|
|
Journal : J. Nat. Prod.
Title : Isolation and structural elucidation of cyclic tetrapeptides from Onychocola sclerotica.
Year : 2012
Volume : 75
Issue : 6
First Page : 1210
Last Page : 1214
Authors : Pérez-Victoria I, Martín J, González-Menéndez V, de Pedro N, El Aouad N, Ortiz-López FJ, Tormo JR, Platas G, Vicente F, Bills GF, Genilloud O, Goetz MA, Reyes F.
Abstract : Three new cyclic tetrapeptides (1-3) have been isolated from the crude fermentation extract of Onychocola sclerotica. The planar structures of 1-3 were elucidated by detailed spectroscopic analyses using one- and two-dimensional NMR experiments and high-resolution mass spectrometry. The absolute configuration of the amino acid residues in each cyclotetrapeptide was established by Marfey's method. Compounds 1-3 displayed activity as cardiac calcium channel blockers (Cav1.2) but did not inhibit the hERG potassium channel and were not cytotoxic. These peptides are the first secondary metabolites ever reported from fungi of the order Arachnomycetales.
|
Inhibition of L-type voltage-dependent Ca2+ channel at 1 uM
|
Homo sapiens
|
100.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Ligand-based design, in silico ADME-Tox filtering, synthesis and biological evaluation to discover new soluble 1,4-DHP-based CFTR activators.
Year : 2012
Volume : 55
First Page : 188
Last Page : 194
Authors : Visentin S, Ermondi G, Medana C, Pedemonte N, Galietta L, Caron G.
Abstract : The altered gating of the mutant CFTR chloride channel cystic fibrosis (CF) may be corrected by small molecules called potentiators. We present a molecular scale simulation system for the discovery of ΔF508-CFTR soluble potentiators. Results report the design, ADME-Tox prediction, synthesis, solubility determination and in vitro biological evaluation of two 1,4-dihydropyridines (DHPs). Compound 1 shows a promising ADME-Tox profile and good potency.
|
Inhibition of mouse Ido2 transfected in HEK293T cells using L-tryptophan as substrate assessed as kynurenine formation at 20 uM after 45 mins by spectrophotometric analysis relative to control
|
Mus musculus
|
55.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Identification of selective inhibitors of indoleamine 2,3-dioxygenase 2.
Year : 2012
Volume : 22
Issue : 24
First Page : 7641
Last Page : 7646
Authors : Bakmiwewa SM, Fatokun AA, Tran A, Payne RJ, Hunt NH, Ball HJ.
Abstract : The kynurenine pathway is responsible for the breakdown of the majority of the essential amino acid, tryptophan (Trp). The first and rate-limiting step of the kynurenine pathway can be independently catalysed by tryptophan 2,3-dioxygenase (Tdo2), indoleamine 2,3-dioxygenase 1 (Ido1) or indoleamine 2,3-dioxygenase 2 (Ido2). Tdo2 or Ido1 enzymatic activity has been implicated in a number of actions of the kynurenine pathway, including immune evasion by tumors. IDO2 is expressed in several human pancreatic cancer cell lines, suggesting it also may play a role in tumorigenesis. Although Ido2 was originally suggested to be a target of the chemotherapeutic agent dextro-1-methyl-tryptophan, subsequent studies suggest this compound does not inhibit Ido2 activity. The development of selective Ido2 inhibitors could provide valuable tools for investigating its activity in tumor development and normal physiology. In this study, a library of Food and Drug Administration-approved drugs was screened for inhibition of mouse Ido2 enzymatic activity. A number of candidates were identified and IC(50) values of each compound for Ido1 and Ido2 were estimated. The Ido2 inhibitors were also tested for inhibition of Tdo2 activity. Our results showed that compounds from a class of drugs used to inhibit proton pumps were the most potent and selective Ido2 inhibitors identified in the library screen. These included tenatoprazole, which exhibited an IC(50) value of 1.8μM for Ido2 with no inhibition of Ido1 or Tdo2 activity detected at a concentration of 100μM tenatoprazole. These highly-selective Ido2 inhibitors will be useful for defining the distinct biological roles of the three Trp-catabolizing enzymes.
|
Displacement of [3H]Nitrendipine from L-type calcium channel dihydropyridine binding site in Wistar rat cerebral cortex after 90 mins
|
Rattus norvegicus
|
0.46
nM
|
|
Displacement of [3H]Nitrendipine from L-type calcium channel dihydropyridine binding site in Wistar rat cerebral cortex after 90 mins
|
Rattus norvegicus
|
0.72
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Cinnamides as selective small-molecule inhibitors of a cellular model of breast cancer stem cells.
Year : 2013
Volume : 23
Issue : 6
First Page : 1834
Last Page : 1838
Authors : Germain AR, Carmody LC, Nag PP, Morgan B, Verplank L, Fernandez C, Donckele E, Feng Y, Perez JR, Dandapani S, Palmer M, Lander ES, Gupta PB, Schreiber SL, Munoz B.
Abstract : A high-throughput screen (HTS) was conducted against stably propagated cancer stem cell (CSC)-enriched populations using a library of 300,718 compounds from the National Institutes of Health (NIH) Molecular Libraries Small Molecule Repository (MLSMR). A cinnamide analog displayed greater than 20-fold selective inhibition of the breast CSC-like cell line (HMLE_sh_Ecad) over the isogenic control cell line (HMLE_sh_eGFP). Herein, we report structure-activity relationships of this class of cinnamides for selective lethality towards CSC-enriched populations.
|
Displacement of [3H]Nitrendipine from L-type calcium channel dihydropyridine binding site in Wistar rat cerebral cortex at 10 uM after 90 mins relative to control
|
Rattus norvegicus
|
-6.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Cinnamides as selective small-molecule inhibitors of a cellular model of breast cancer stem cells.
Year : 2013
Volume : 23
Issue : 6
First Page : 1834
Last Page : 1838
Authors : Germain AR, Carmody LC, Nag PP, Morgan B, Verplank L, Fernandez C, Donckele E, Feng Y, Perez JR, Dandapani S, Palmer M, Lander ES, Gupta PB, Schreiber SL, Munoz B.
Abstract : A high-throughput screen (HTS) was conducted against stably propagated cancer stem cell (CSC)-enriched populations using a library of 300,718 compounds from the National Institutes of Health (NIH) Molecular Libraries Small Molecule Repository (MLSMR). A cinnamide analog displayed greater than 20-fold selective inhibition of the breast CSC-like cell line (HMLE_sh_Ecad) over the isogenic control cell line (HMLE_sh_eGFP). Herein, we report structure-activity relationships of this class of cinnamides for selective lethality towards CSC-enriched populations.
|
Inhibition of sodium fluorescein uptake in OATP1B1-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
341.9
%
|
|
Journal : Mol. Pharmacol.
Title : Structure-based identification of OATP1B1/3 inhibitors.
Year : 2013
Volume : 83
Issue : 6
First Page : 1257
Last Page : 1267
Authors : De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP.
Abstract : Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1- or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 µM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration-dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 µM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.
|
Inhibition of sodium fluorescein uptake in OATP1B3-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
77.72
%
|
|
Journal : Mol. Pharmacol.
Title : Structure-based identification of OATP1B1/3 inhibitors.
Year : 2013
Volume : 83
Issue : 6
First Page : 1257
Last Page : 1267
Authors : De Bruyn T, van Westen GJ, Ijzerman AP, Stieger B, de Witte P, Augustijns PF, Annaert PP.
Abstract : Several recent studies show that inhibition of the hepatic transport proteins organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) can result in clinically relevant drug-drug interactions (DDI). To avoid late-stage development drug failures due to OATP1B-mediated DDI, predictive in vitro and in silico methods should be implemented at an early stage of the drug candidate evaluation process. In the present study, we first developed a high-throughput in vitro transporter inhibition assay for the OATP1B subfamily. A total of 2000 compounds were tested as potential modulators of the uptake of the OATP1B substrate sodium fluorescein, in OATP1B1- or 1B3-transfected Chinese hamster ovary cells. At an equimolar substrate-inhibitor concentration of 10 µM, 212 and 139 molecules were identified as OATP1B1 and OATP1B3 inhibitors, respectively (minimum 50% inhibition). For 69 compounds, previously not identified as OATP1B inhibitors, concentration-dependent inhibition was also determined, yielding Ki values ranging from 0.06 to 6.5 µM. Based on these in vitro data, we subsequently developed a proteochemometrics-based in silico model, which predicted OATP1B inhibitors in the test group (20% of the dataset) with high specificity (86%) and sensitivity (78%). Moreover, several physicochemical compound properties and substructures related to OATP1B1/1B3 inhibition or inactivity were identified. Finally, model performance was prospectively verified with a set of 54 compounds not included in the original dataset. This validation indicated that 80 and 74% of the compounds were correctly classified for OATP1B1 and OATP1B3 inhibition, respectively.
|
Vasodilative activity in isolated Sprague-Dawley rat mesenteric arterial ring assessed as reduction in KCl-induced contraction by wire myograph method
|
Rattus norvegicus
|
3.981
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of novel 3-benzylquinazolin-4(3H)-ones as potent vasodilative agents.
Year : 2014
Volume : 24
Issue : 24
First Page : 5597
Last Page : 5601
Authors : Zuo SJ, Li S, Yu RH, Zheng GX, Cao YX, Zhang SQ.
Abstract : In the present study, a series of 3-benzylquinazolin-4(3H)-ones were synthesized and characterized. Their vasodilative effects were evaluated by wire myograph on isolated rat mesenteric arterial ring induced contraction with 60mM KCl. The SAR of target compounds was discussed preliminarily. Among these compounds, 2a and 2c displayed potent vasodilatation action and could compete significantly the rat mesenteric arterial rings induced contraction with phenylephrine. Compounds 2a and 2c were further tested for their antihypertensive effects in SHR by oral administration. The results indicated that 2a and 2c could reduce significantly both diastolic and systolic blood pressure. Moreover, 2c displayed antihypertensive effect in a dose dependent manner, and could maintain the effects for 6h at a dosage of 4.0mg/kg. These findings suggest that the title compounds are novel vasodilative agents, representing a novel series of promising antihypertensive agents.
|
Inhibition of voltage-gated L-type Ca channel (species unknown)
|
None
|
0.35
nM
|
|
Journal : Cardiovasc. Res.
Title : Simulation of multiple ion channel block provides improved early prediction of compounds' clinical torsadogenic risk.
Year : 2011
Volume : 91
First Page : 53
Last Page : 61
Authors : Mirams GR, Cui Y, Sher A, Fink M, Cooper J, Heath BM, McMahon NC, Gavaghan DJ, Noble D.
Abstract : The level of inhibition of the human Ether-à-go-go-related gene (hERG) channel is one of the earliest preclinical markers used to predict the risk of a compound causing Torsade-de-Pointes (TdP) arrhythmias. While avoiding the use of drugs with maximum therapeutic concentrations within 30-fold of their hERG inhibitory concentration 50% (IC(50)) values has been suggested, there are drugs that are exceptions to this rule: hERG inhibitors that do not cause TdP, and drugs that can cause TdP but are not strong hERG inhibitors. In this study, we investigate whether a simulated evaluation of multi-channel effects could be used to improve this early prediction of TdP risk.We collected multiple ion channel data (hERG, Na, L-type Ca) on 31 drugs associated with varied risks of TdP. To integrate the information on multi-channel block, we have performed simulations with a variety of mathematical models of cardiac cells (for rabbit, dog, and human ventricular myocyte models). Drug action is modelled using IC(50) values, and therapeutic drug concentrations to calculate the proportion of blocked channels and the channel conductances are modified accordingly. Various pacing protocols are simulated, and classification analysis is performed to evaluate the predictive power of the models for TdP risk. We find that simulation of action potential duration prolongation, at therapeutic concentrations, provides improved prediction of the TdP risk associated with a compound, above that provided by existing markers.The suggested calculations improve the reliability of early cardiac safety assessments, beyond those based solely on a hERG block effect.
|
Inhibition of Cav1.2 current measured using QPatch automatic path clamp system in CHO cells expressing Cav1.2, beta-2 and alpha-2/delta-1 subunits
|
Cricetulus griseus
|
30.0
nM
|
|
Journal : Scientific Reports
Title : MICE models: superior to the HERG model in predicting Torsade de Pointes.
Year : 2013
Volume : 3
First Page : 1
Last Page : 7
Authors : Kramer J, Obejero-Paz CA, Myatt G, Kuryshev YA, Bruening-Wright A, Verducci JS, Brown AM.
Abstract : Drug-induced block of the cardiac hERG (human Ether-à-go-go-Related Gene) potassium channel delays cardiac repolarization and increases the risk of Torsade de Pointes (TdP), a potentially lethal arrhythmia. A positive hERG assay has been embraced by regulators as a non-clinical predictor of TdP despite a discordance of about 30%. To test whether assaying concomitant block of multiple ion channels (Multiple Ion Channel Effects or MICE) improves predictivity we measured the concentration-responses of hERG, Nav1.5 and Cav1.2 currents for 32 torsadogenic and 23 non-torsadogenic drugs from multiple classes. We used automated gigaseal patch clamp instruments to provide higher throughput along with accuracy and reproducibility. Logistic regression models using the MICE assay showed a significant reduction in false positives (Type 1 errors) and false negatives (Type 2 errors) when compared to the hERG assay. The best MICE model only required a comparison of the blocking potencies between hERG and Cav1.2.
|
Vasodilative activity in isolated Sprague-Dawley rat Superior mesenteric arterial ring assessed as reduction in KCl-induced contraction by wire myograph method relative to control
|
Rattus norvegicus
|
0.3162
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of novel 2-benzylisoquinolin-1(2H)-ones as potent vasodilative agents.
Year : 2015
Volume : 25
Issue : 24
First Page : 5808
Last Page : 5812
Authors : Kang BR, Li S, Mao S, Cao YX, Zhang SQ.
Abstract : 2-Benzylisoquinolin-1(2H)-ones has been proposed as vasodilative agents on the basis of scaffold hopping. In the present study, a series of 2-benzylisoquinolin-1(2H)-ones were synthesized. Their vasodilative effects were evaluated by wire myograph on isolated rat mesenteric arterial ring induced contraction with 60mM KCl. The structure-activity relationships of target compounds were discussed. Among these compounds, C7 and C8 displayed potent vasodilative effects and significantly inhibited the contraction of rat mesenteric arterial rings induced by phenylephrine. The antihypertensive effects of compounds C7 and C8 on SHR were further evaluated. The results indicated that oral administrational C7 and C8 can significantly reduce both diastolic and systolic blood pressure in a dose-dependent manner. Moreover, C7 maintained the effects for 4h at a dosage of 4.0mg/kg. These findings suggest that the title compounds can serve as novel vasodilative agents and promising antihypertensive agents.
|
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
|
11.21
%
|
|
|
Antibacterial activity against Escherichia coli ATCC 25922 (CO-ADD:GN_001); MIC in CAMBH media using NBS plates, by OD(600)
|
Escherichia coli
|
-2.58
%
|
|
|
Antibacterial activity against Klebsiella pneumoniae MDR ATCC 70063 (CO-ADD:GN_003); MIC in CAMBH media using NBS plates, by OD(600)
|
Klebsiella pneumoniae
|
3.96
%
|
|
|
Antibacterial activity against Pseudomonas aeruginosa ATCC 27853 (CO-ADD:GN_042); MIC in CAMBH media using NBS plates, by OD(600)
|
Pseudomonas aeruginosa
|
7.78
%
|
|
|
Antibacterial activity against Acinetobacter baumannii ATCC 19606 (CO-ADD:GN_034); MIC in CAMBH media using NBS plates, by OD600
|
Acinetobacter baumannii
|
8.52
%
|
|
|
Antifungal activity against Candida albicans ATCC 90028 (CO-ADD:FG_001); MIC in YNB media using NBS plates, by OD630
|
Candida albicans
|
3.79
%
|
|
|
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
|
-6.79
%
|
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
11.19
%
|
|
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
|
0.3
%
|
|
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
|
0.3
%
|
|
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.
