|
Compound was evaluated for the inhibition of gastrin-stimulated gastric acid secretion in conscious heidenhain pouch dogs when administered 1 mg/kg perorally
|
Canis lupus familiaris
|
53.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Anti-Helicobacter pylori agents. 2. Structure activity relationships in a new series of 2-alkylguanidino-4-furylthiazoles.
Year : 1998
Volume : 8
Issue : 11
First Page : 1307
Last Page : 1312
Authors : Katsura Y, Nishino S, Tomishi T, Sakane K, Matsumoto Y, Ishikawa H, Takasugi H.
Abstract : SAR for antimicrobial activity against H. pylori was investigated in a new series of 2-alkylguanidino-4-furylthiazoles. Of the compounds obtained, cyclohexylmethyl and ethoxyethyl derivatives were identified as a novel class of anti-H. pylori agents which possessed potent and selective antimicrobial activity against H. pylori. These compounds also showed gastric antisecretory activity.
|
Evaluated against tetragastrin stimulated gastric acid secretion in conscious Hiedenhain-pouch dogs at a dose of 22 mg/kg, po
|
Canis lupus familiaris
|
22.0
%
|
|
Journal : J. Med. Chem.
Title : Studies on antiulcer drugs. 7. 2-Guanidino-4-pyridylthiazoles as histamine H2-receptor antagonists with potent gastroprotective effects against nonsteroidal antiinflammatory drug-induced injury.
Year : 1994
Volume : 37
Issue : 1
First Page : 57
Last Page : 66
Authors : Katsura Y, Inoue Y, Tomishi T, Ishikawa H, Takasugi H.
Abstract : A series of 2-guanidino-4-pyridylthiazole derivatives were synthesized and evaluated for anti-aspirin-ulcer, gastric antisecretory, and histamine-H2-receptor-antagonist activities. Several compounds showed superior anti-aspirin-ulcer activity to that of clinically used H2-antagonists in the rat. Among them, 4-[6-(acetamidomethyl)pyridin-2-yl]-2-guanidinothiazole (8) demonstrated potent inhibitory activities against gastric lesions caused by two kinds of nonsteroidal antiinflammatory drugs, aspirin and indomethacin, respectively, in addition to strong antisecretory activity. Compound 8 possessed a preventable ability for the aspirin-induced reduction of the gastric mucosal blood flow at an intragastric administration of 32 mg/kg in the rat. On the other hand, famotidine (32 mg/kg) exhibited no significant effect and ranitidine (100 mg/kg) aggravated the blood flow in this system.
|
Histamine-stimulated gastric acid secretion in Heidenhain pouch dog at 1uM/Kg, on iv administration of the compound
|
Canis lupus familiaris
|
1.7
%
|
|
Journal : J. Med. Chem.
Title : Reversible inhibitors of the gastric (H+/K+)-ATPase. 5. Substituted 2,4-diaminoquinazolines and thienopyrimidines.
Year : 1995
Volume : 38
Issue : 14
First Page : 2763
Last Page : 2773
Authors : Ife RJ, Brown TH, Blurton P, Keeling DJ, Leach CA, Meeson ML, Parsons ME, Theobald CJ.
Abstract : Quinazolines bearing a secondary 4-(arylamino) substituent demonstrate an SAR for inhibition of the gastric (H+/K+)-ATPase different from the previously described 3-acylquinolines, suggesting that, although these compounds are also K(+)-competitive, they probably bind to the enzyme in a different orientation. Compounds bearing a tertiary 4-(arylamino) substituent, however, in particular 4-(N-methylarylamino), appear to possess an SAR quite similar to the 3-acylquinolines. We show that this arises from the effect of the N-methylation, which is to orientate the 4-(arylamino) substituent syn to C5, analogous to the 3-acylquinolines. Compounds possessing both a 4-(N-methylarylamino) substituent and a 2-(arylamino) substituent proved to be very potent, K(+)-competitive inhibitors of K(+)-stimulated ATPase activity with Ki values down to 12 nM. Some compounds also proved to be effective inhibitors of stimulated acid secretion in both the rat and dog when dosed intravenously. However, although a number of these demonstrated activity after oral administration in the dog, the level and variability precluded further evaluation.
|
Histamine-stimulated gastric acid secretion in Heidenhain pouch dog at 4uM/Kg, on iv administration of the compound
|
Canis lupus familiaris
|
8.5
%
|
|
Journal : J. Med. Chem.
Title : Reversible inhibitors of the gastric (H+/K+)-ATPase. 5. Substituted 2,4-diaminoquinazolines and thienopyrimidines.
Year : 1995
Volume : 38
Issue : 14
First Page : 2763
Last Page : 2773
Authors : Ife RJ, Brown TH, Blurton P, Keeling DJ, Leach CA, Meeson ML, Parsons ME, Theobald CJ.
Abstract : Quinazolines bearing a secondary 4-(arylamino) substituent demonstrate an SAR for inhibition of the gastric (H+/K+)-ATPase different from the previously described 3-acylquinolines, suggesting that, although these compounds are also K(+)-competitive, they probably bind to the enzyme in a different orientation. Compounds bearing a tertiary 4-(arylamino) substituent, however, in particular 4-(N-methylarylamino), appear to possess an SAR quite similar to the 3-acylquinolines. We show that this arises from the effect of the N-methylation, which is to orientate the 4-(arylamino) substituent syn to C5, analogous to the 3-acylquinolines. Compounds possessing both a 4-(N-methylarylamino) substituent and a 2-(arylamino) substituent proved to be very potent, K(+)-competitive inhibitors of K(+)-stimulated ATPase activity with Ki values down to 12 nM. Some compounds also proved to be effective inhibitors of stimulated acid secretion in both the rat and dog when dosed intravenously. However, although a number of these demonstrated activity after oral administration in the dog, the level and variability precluded further evaluation.
|
Maximum percent inhibition of acid output in penta gastrin-stimulated Heidenhain pouch dogs at a dose of 10 mg/kg, given intravenously (iv).
|
Canis lupus familiaris
|
1.02
%
|
|
Journal : J. Med. Chem.
Title : Bioisosteric prototype design of biaryl imidazolyl and triazolyl competitive histamine H2-receptor antagonists.
Year : 1986
Volume : 29
Issue : 11
First Page : 2154
Last Page : 2163
Authors : Lipinski CA, LaMattina JL, Oates PJ.
Abstract : The structural relationship of the competitive histamine H2-receptor antagonist 3-amino-5-(2-amino-4-pyridyl)-1,2,4-triazole (1) to the agonist histamine and to antagonists of the cimetidine type was explored by the design and synthesis of four series of bioisosterically designed prototypes. Biological data from these series was best interpreted as indicating a similarity between the imidazole moiety of histamine and cimetidine and the 2-amino-4-pyridyl moiety of 1. On the basis of this data, sequential replacement of 2-amino-4-pyridyl by 2-[(dimethylamino)methyl]-5-furyl and 2-guanidino-4-triazolyl moieties led to a structurally more potent series of biaryl histamine H2-receptor antagonists. The best of these, 2-methyl-4-(2-guanidino-4-thiazolyl)imidazole (29, CP-57,361-1) was 120 times more potent as a histamine H2-receptor antagonist than 1.
|
Inhibition of histamine stimulated chronotropic response in isolated guinea pig right atrium (1*10e-6 g/mL)
|
Cavia porcellus
|
43.0
%
|
|
Journal : J. Med. Chem.
Title : Anti-Helicobacter pylori agents. 4. 2-(Substituted guanidino)-4-phenylthiazoles and some structurally rigid derivatives.
Year : 2000
Volume : 43
Issue : 17
First Page : 3315
Last Page : 3321
Authors : Katsura Y, Tomishi T, Inoue Y, Sakane K, Matsumoto Y, Morinaga C, Ishikawa H, Takasugi H.
Abstract : In order to find a new class of anti-Helicobacter pylori (H. pylori) agents, a series of 4-[(3-acetamido)phenyl]-2-(substituted guanidino)thiazoles and some structurally rigid analoges were synthesized and evaluated for antimicrobial activity against H. pylori. Among the compounds obtained, high anti-H. pyrori activities were observed in benzyl derivative 34 (MIC = 0.025 microg/mL) and phenethyl derivatives 35 and 36 (MIC = 0.037 microg/mL and 0.017 microg/mL). Though alkyl derivatives generally showed lower activity, the 2-methoxyethyl derivative 28 preserved significant activity (MIC = 0.32 microg/mL) and also exhibited more potent gastric antisecretory activity than ranitidine. Structural restriction by bridging between the thiazole and the phenyl rings with an alkyl chain did not improve the activity in this series.
|
Inhibition of histamine-stimulated chronotropic response in the isolated guinea pig right atrium at 1*10e-6 g/mL
|
Cavia porcellus
|
43.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Anti-Helicobacter pylori agents. 2. Structure activity relationships in a new series of 2-alkylguanidino-4-furylthiazoles.
Year : 1998
Volume : 8
Issue : 11
First Page : 1307
Last Page : 1312
Authors : Katsura Y, Nishino S, Tomishi T, Sakane K, Matsumoto Y, Ishikawa H, Takasugi H.
Abstract : SAR for antimicrobial activity against H. pylori was investigated in a new series of 2-alkylguanidino-4-furylthiazoles. Of the compounds obtained, cyclohexylmethyl and ethoxyethyl derivatives were identified as a novel class of anti-H. pylori agents which possessed potent and selective antimicrobial activity against H. pylori. These compounds also showed gastric antisecretory activity.
|
inhibition of the histamine stimulated chronic response in the isolated guinea pig right atrium at 1x 10 e-6 g/mL
|
Cavia porcellus
|
43.0
%
|
|
Journal : J. Med. Chem.
Title : Anti-Helicobacter pylori agents. 1. 2-(Alkylguanidino)-4-furylthiazoles and related compounds.
Year : 1997
Volume : 40
Issue : 16
First Page : 2462
Last Page : 2465
Authors : Katsura Y, Tomishi T, Inoue Y, Sakane K, Matsumoto Y, Ishikawa H, Takasugi H.
Abstract : A series of 2-(alkylguanidino)-4-[5-(acetamidomethyl)furan-2-yl]thiazoles and related compounds were synthesized and evaluated for antimicrobial activity against Helicobacter pylori, inhibitory effect on gastric acid secretion, and histamine H2-receptor antagonist activity. Introduction of alkyl substituents on the guanidino moiety resulted in a significant increase in antimicrobial activity, which was associated with the alkyl chain length. Of the compounds obtained, the n-hexylguanidino derivative 13 demonstrated a 250-fold improvement in activity (MIC = 0.11 micrograms/mL) over the unsubstituted guanidino derivative 7. Alkyl-substituted guanidino derivatives also displayed gastric antisecretion and H2-antagonist activities. However, a simple correlation between the alkyl chain length and the activities was not found in these assays. Replacement of the guanidine with other bioisosteric groups (thiourea, urea, or (dimethylamino)methyl) resulted in loss of all activities tested. Thus the guanidino moiety was found to be essential for activity in this series of compounds.
|
Evaluated in vitro for Histamine H2 receptor inhibition using the dimaprit stimulated chronotropic response of the guinea pig atrium
|
Cavia porcellus
|
501.19
nM
|
|
Journal : J. Med. Chem.
Title : Conformational requirements for histamine H2-receptor inhibitors: a structure-activity study of phenylene analogues related to cimetidine and tiotidine.
Year : 1983
Volume : 26
Issue : 2
First Page : 140
Last Page : 144
Authors : Hoffman JM, Pietruszkiewicz AM, Habecker CN, Phillips BT, Bolhofer WA, Cragoe EJ, Torchiana ML, Lumma WC, Baldwin JJ.
Abstract : Two series of compounds related to cimetidine and tiotidine were synthesized as part of a study to evaluate the importance of conformational parameters in binding at histamine H2 receptors. The flexible methylthioethyl connecting chain was replaced by a conformationally restricting phenylene unit. These compounds were evaluated for antagonism of the dimaprit-stimulated chronotropic response in the guinea pig atrium and inhibition of histamine stimulated secretion of gastric acid in the dog. In both series, biological activity is markedly dependent on the m-phenylene regioisomers. Histamine H2-receptor activity is retained in both series; however, in the tiotidine series, gastric antisecretory activity is significantly improved. Regardless of the end group, N-cyanoguanidine 1,1-diamino-2-nitroethene or 3,4-diamino-1,2,5-thiadiazole 1-oxide, each 3 3-(2-guanidino-4-thiazolyl)phenyl analogue was ca. 8 and 90 times more potent intravenously than tiotidine and cimetidine, respectively. The electronic influences of the phenylene unit on biological activity were also evaluated. It was concluded that the geometric constraints imposed by the m-phenylene connecting element were more important than electronic factors in binding events at the histamine H2 receptor.
|
In vitro inhibition of Histamine H2 receptor by measuring its ability to block the histamine-stimulated adenylate cyclase of guinea pig hippocampal homogenate
|
Cavia porcellus
|
501.19
nM
|
|
Journal : J. Med. Chem.
Title : Inhibitors of gastric acid secretion: 3,4-diamino-1,2,5-thiadiazole 1-oxides and 1,1-dioxides as urea equivalents in a series of histamine H2-receptor antagonists.
Year : 1982
Volume : 25
Issue : 3
First Page : 207
Last Page : 210
Authors : Lumma WC, Anderson PS, Baldwin JJ, Bolhofer WA, Habecker CN, Hirshfield JM, Pietruszkiewicz AM, Randall WC, Torchiana ML, Britcher SF, Clineschmidt BV, Denny GH, Hirschmann R, Hoffman MJ, Phillips BT, Streeter KB.
|
Histamine H2 receptor antagonistic activity
|
Cavia porcellus
|
3.7
ug.mL-1
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis of a piperidinomethylthiophene derivative as H2-antagonist with inhibitory activity against Helicobacter pylori
Year : 1996
Volume : 6
Issue : 15
First Page : 1795
Last Page : 1798
Authors : Kojima K, Nakajima K, Kurata H, Tabata K, Utsui Y
|
H2 receptor antagonistic activity against histamine stimulated chronotropic response in isolated guinea pig right atrium at 1x10E-6 g/mL.
|
Cavia porcellus
|
43.0
%
|
|
Journal : J. Med. Chem.
Title : Studies on antiulcer drugs. 7. 2-Guanidino-4-pyridylthiazoles as histamine H2-receptor antagonists with potent gastroprotective effects against nonsteroidal antiinflammatory drug-induced injury.
Year : 1994
Volume : 37
Issue : 1
First Page : 57
Last Page : 66
Authors : Katsura Y, Inoue Y, Tomishi T, Ishikawa H, Takasugi H.
Abstract : A series of 2-guanidino-4-pyridylthiazole derivatives were synthesized and evaluated for anti-aspirin-ulcer, gastric antisecretory, and histamine-H2-receptor-antagonist activities. Several compounds showed superior anti-aspirin-ulcer activity to that of clinically used H2-antagonists in the rat. Among them, 4-[6-(acetamidomethyl)pyridin-2-yl]-2-guanidinothiazole (8) demonstrated potent inhibitory activities against gastric lesions caused by two kinds of nonsteroidal antiinflammatory drugs, aspirin and indomethacin, respectively, in addition to strong antisecretory activity. Compound 8 possessed a preventable ability for the aspirin-induced reduction of the gastric mucosal blood flow at an intragastric administration of 32 mg/kg in the rat. On the other hand, famotidine (32 mg/kg) exhibited no significant effect and ranitidine (100 mg/kg) aggravated the blood flow in this system.
|
Antagonistic activity against Histamine H2 receptor expressed as the charge of receptor sensitivity was determined at pH 7.0
|
Cavia porcellus
|
954.99
nM
|
|
Journal : J. Med. Chem.
Title : Studies on the active molecular species of the H2 receptor antagonists cimetidine and mifentidine.
Year : 1987
Volume : 30
Issue : 1
First Page : 208
Last Page : 211
Authors : Haaksma EE, Rademaker B, Kramer K, Eriks JC, Bast A, Timmerman H.
Abstract : The N'-(4-1H-imidazol-4-ylphenyl)formamidines were recently introduced as a new class of active H2 antagonists; the authors of the compounds (Donetti et al. of de Angeli, Italy) have suggested that these compounds interact with the H2 receptor through their monocations. This is at variance with the model proposed for cimetidine by the SK&F (Smith Kline & French, UK) group who proposed the neutral molecule as the species active at the H2 receptor. In the present study we have investigated the issue whether the neutral or charged species is the active one by measuring the pA2 values of mifentidine and cimetidine at different pH values. Changing the pH will influence the species equilibria of both compounds and thereby affect their activity. The activity changes measured for both compounds are consistent with the proposition that cimetidine as well as mifentidine elicit their activity through their neutral species.
|
Antagonistic activity against Histamine H2 receptor expressed as the charge of receptor sensitivity was determined at pH 7.4
|
Cavia porcellus
|
398.11
nM
|
|
Journal : J. Med. Chem.
Title : Studies on the active molecular species of the H2 receptor antagonists cimetidine and mifentidine.
Year : 1987
Volume : 30
Issue : 1
First Page : 208
Last Page : 211
Authors : Haaksma EE, Rademaker B, Kramer K, Eriks JC, Bast A, Timmerman H.
Abstract : The N'-(4-1H-imidazol-4-ylphenyl)formamidines were recently introduced as a new class of active H2 antagonists; the authors of the compounds (Donetti et al. of de Angeli, Italy) have suggested that these compounds interact with the H2 receptor through their monocations. This is at variance with the model proposed for cimetidine by the SK&F (Smith Kline & French, UK) group who proposed the neutral molecule as the species active at the H2 receptor. In the present study we have investigated the issue whether the neutral or charged species is the active one by measuring the pA2 values of mifentidine and cimetidine at different pH values. Changing the pH will influence the species equilibria of both compounds and thereby affect their activity. The activity changes measured for both compounds are consistent with the proposition that cimetidine as well as mifentidine elicit their activity through their neutral species.
|
Antagonistic activity against Histamine H2 receptor expressed as the charge of receptor sensitivity was determined at pH 7.8
|
Cavia porcellus
|
371.54
nM
|
|
Journal : J. Med. Chem.
Title : Studies on the active molecular species of the H2 receptor antagonists cimetidine and mifentidine.
Year : 1987
Volume : 30
Issue : 1
First Page : 208
Last Page : 211
Authors : Haaksma EE, Rademaker B, Kramer K, Eriks JC, Bast A, Timmerman H.
Abstract : The N'-(4-1H-imidazol-4-ylphenyl)formamidines were recently introduced as a new class of active H2 antagonists; the authors of the compounds (Donetti et al. of de Angeli, Italy) have suggested that these compounds interact with the H2 receptor through their monocations. This is at variance with the model proposed for cimetidine by the SK&F (Smith Kline & French, UK) group who proposed the neutral molecule as the species active at the H2 receptor. In the present study we have investigated the issue whether the neutral or charged species is the active one by measuring the pA2 values of mifentidine and cimetidine at different pH values. Changing the pH will influence the species equilibria of both compounds and thereby affect their activity. The activity changes measured for both compounds are consistent with the proposition that cimetidine as well as mifentidine elicit their activity through their neutral species.
|
In vitro inhibitory activity against histamine H2-receptor in isolated Guinea pig right atria.
|
Cavia porcellus
|
263.03
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis and antiulcer activity of N-substituted N'-[3-[3-(piperidinomethyl)phenoxy]propyl]ureas: histamine H2-receptor antagonists with a potent mucosal protective activity.
Year : 1992
Volume : 35
Issue : 13
First Page : 2446
Last Page : 2451
Authors : Miyashita M, Matsumoto T, Matsukubo H, Iinuma F, Taga F, Sekiguchi H, Hamada K, Okamura K, Nishino K.
Abstract : As an aim toward developing new antiulcer agents, new N-substituted N'-[3-[3-(piperidinomethyl)phenoxy]propyl]ureas were synthesized and evaluated for histamine H2-receptor antagonistic, gastric antisecretory, and gastric mucosal protective activities. A QSAR study showed that the most favorable N-substituents were electron-donating straight-chain alkyl groups of short length such as ethyl group from the viewpoint of dual action, i.e., gastric antisecretory and mucosal protective actions. Among the ureas studied, compounds 4, 5, and 8-10 were selected as candidates for further study.
|
Inhibition of [125I]APT binding to H2 receptors in guinea pig cerebral membranes.
|
Cavia porcellus
|
302.0
nM
|
|
Journal : J. Med. Chem.
Title : Iodoaminopotentidine and related compounds: a new class of ligands with high affinity and selectivity for the histamine H2 receptor.
Year : 1992
Volume : 35
Issue : 12
First Page : 2231
Last Page : 2238
Authors : Hirschfeld J, Buschauer A, Elz S, Schunack W, Ruat M, Traiffort E, Schwartz JC.
Abstract : The synthesis and biological evaluation of a new class of histamine H2 antagonists with N-cyano-N'-[omega-[3-(1-piperidinylmethyl)phenoxy] alkyl]guanidine partial structure are described as part of an extensive research program to find model compounds for the development of new radioligands with high H2 affinity and specific activity. High receptor affinity is achieved by an additional (substituted) aromatic ring, which is connected with the third guanidine N by a carbon chain spacer and an amine, carboxamide, ester, or sulfonamide link ("polar group"). In functional studies for H2 antagonistic activity and other pharmacological actions [e.g. H1 antihistaminic, antimuscarinic, antiadrenergic (alpha 1, beta 1), 5-HT2 blocking activity] in the isolated guinea pig atrium and ileum and rat aorta and tail artery, the compounds proved to be highly potent and selective histamine H2 receptor antagonists. The H2 antagonistic activity is mainly depending on the length of both the N'-alkyl chain (chain A) and the N"-spacer (chain B). Compounds with a C3 chain A and a C2 chain B are most potent in the preferred group of substances, i.e., the carboxamide series. A wide variety of substituents at the aromatic ring is tolerated, among them iodine, amino, and azido groups. These compounds are up to 32 times more potent than cimetidine in the isolated guinea pig right atrium. The replacement of the carboxamide by an ester group (44c) is well tolerated, while replacement of the cyanoguanidine by an urea group results in nearly 100-fold decrease in activity (46c,e). The iodinated benzamides are among the most potent H2 antagonists known so far. The [125I]-labeled form of 31f ([125I]iodoaminopotentidine, [125I]-N-[2-(4-amino-3-iodobenzamido) ethyl]-N'-cyano-N"-[3-[3-(1-piperidinylmethyl) phenoxy]propyl]guanidine) and its photolabile analogue 31h ([125I]iodoazidopotentidine, [125I]-N-[2-(4-azido-3- iodobenzamido)ethyl]-N'-cyano-N"-[3-[3-(1-piperidinyl-methyl)pheno xy] propyl]guanidine) proved to be useful probes for reversible and irreversible labeling of the histamine H2 receptor. Radioligand binding studies in guinea pig cerebral membranes revealed considerably higher H2 receptor affinity for 31f (pKi = 9.15), 31h (pKi = 8.58), and some analogues than functional experiments (guinea pig atrium), presumably reflecting an easier access to the H2 receptors in membranes.
|
Histamine H2 receptor antagonism in isolated guinea pig right atrium at concentration of 1*10e-6 g/mL of histamine hydrochloride
|
Cavia porcellus
|
43.0
%
|
|
Journal : J. Med. Chem.
Title : Anti-Helicobacter pylori agents. 3. 2-[(Arylalkyl)guanidino]-4-furylthiazoles.
Year : 1999
Volume : 42
Issue : 15
First Page : 2920
Last Page : 2926
Authors : Katsura Y, Nishino S, Ohno M, Sakane K, Matsumoto Y, Morinaga C, Ishikawa H, Takasugi H.
Abstract : A series of 2-[(arylalkyl)guanidino]-4-[(5-acetamidomethyl)furan-2-yl]thiazole s and some 4-acetamidomethyl positional isomers were synthesized and evaluated for antimicrobial activity against Helicobacter pylori. Among the compounds that had potent antimicrobial activity (MIC < 0. 1 microgram/mL), compounds 31 and 36 additionally possessed H2 antagonist and gastric antisecretory activities. Though compound 51, an analogue incorporating a methyl group onto the furan nucleus of 36, and compound 54, a positional isomer of 51, also showed potent anti-H. pylori activity, the H2 antagonism profile was eliminated from these compounds. Thus, two types of potent anti-H. pylori agents could be derived from the same scaffold.
|
Antagonistic activity for inhibition of histamine H2 receptor from anesthetized rats
|
None
|
251.19
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis, and pharmacological evaluation of dual histamine H2 and gastrin receptor antagonists
Year : 1996
Volume : 6
Issue : 13
First Page : 1421
Last Page : 1426
Authors : Kawanishi Y, Ishihara S, Tsushima T, Seno K, Miyagoshi M, Hagishita S, Ishikawa M, Shima N, Shimamura M, Ishihara Y
|
Antagonistic activity by inhibition histamine H2 receptor from rats.
|
None
|
251.19
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and pharmacological evaluation of highly potent dual histamine H2 and gastrin receptor antagonists
Year : 1996
Volume : 6
Issue : 13
First Page : 1427
Last Page : 1430
Authors : Kawanishi Y, Ishihara S, Tsushima T, Seno K, Miyagoshi M, Hagishita S, Ishikawa M, Shima N, Shimamura M, Ishihara Y
|
Percentage inhibition for muscarinic acetylcholine receptor at concentration 10 e-5M.
|
None
|
2.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and antiulcer activity of 5,11-dihydro[1]benzoxepino[3,4-b]pyridines.
Year : 1988
Volume : 31
Issue : 4
First Page : 779
Last Page : 785
Authors : Kumazawa T, Harakawa H, Obase H, Oiji Y, Tanaka H, Shuto K, Ishii A, Oka T, Nakamizo N.
Abstract : A series of substituted 5,11-dihydro[1]benzoxepino[3,4-b]pyridines was synthesized and evaluated for antiulcer activity in water immersion/restrained stress ulcer assay in rats. Structure-activity relationships are described. Most of the tested compounds exhibited low affinity to the muscarinic acetylcholine receptor. The molecular features for the best activities are the 2-(diethylamino)ethylenediamine group at the 5-position of the oxepin ring and an oxepin skeleton rather than a thiepin or a pyran skeleton. Methyl and chlorine substitution on the benzene ring reduced the activity. Compound 11, 5-[[2-(diethylamino)ethyl]amino]-5,11-dihydro[1]benzoxepino [3,4-b]pyridine trihydrochloride was selected for further evaluation. Synthesis and antiulcer activity of optically active 11 is described. There were no statistically significant differences between (+)-, (-)-, and (+/-)-11. Compound 11 showed weak antisecretory activity in pylorus-ligated rats. It is now under clinical evaluation as KW 5805.
|
Percentage inhibition for muscarinic acetylcholine receptor at concentration 10e-6 M.
|
None
|
2.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and antiulcer activity of 5,11-dihydro[1]benzoxepino[3,4-b]pyridines.
Year : 1988
Volume : 31
Issue : 4
First Page : 779
Last Page : 785
Authors : Kumazawa T, Harakawa H, Obase H, Oiji Y, Tanaka H, Shuto K, Ishii A, Oka T, Nakamizo N.
Abstract : A series of substituted 5,11-dihydro[1]benzoxepino[3,4-b]pyridines was synthesized and evaluated for antiulcer activity in water immersion/restrained stress ulcer assay in rats. Structure-activity relationships are described. Most of the tested compounds exhibited low affinity to the muscarinic acetylcholine receptor. The molecular features for the best activities are the 2-(diethylamino)ethylenediamine group at the 5-position of the oxepin ring and an oxepin skeleton rather than a thiepin or a pyran skeleton. Methyl and chlorine substitution on the benzene ring reduced the activity. Compound 11, 5-[[2-(diethylamino)ethyl]amino]-5,11-dihydro[1]benzoxepino [3,4-b]pyridine trihydrochloride was selected for further evaluation. Synthesis and antiulcer activity of optically active 11 is described. There were no statistically significant differences between (+)-, (-)-, and (+/-)-11. Compound 11 showed weak antisecretory activity in pylorus-ligated rats. It is now under clinical evaluation as KW 5805.
|
Inhibition of P-gp was determined using rhodamine-assay in human CaCo-2 cells
|
None
|
4.0
%
|
|
Journal : J. Med. Chem.
Title : Comparison of in vitro P-glycoprotein screening assays: recommendations for their use in drug discovery.
Year : 2003
Volume : 46
Issue : 9
First Page : 1716
Last Page : 1725
Authors : Schwab D, Fischer H, Tabatabaei A, Poli S, Huwyler J.
Abstract : The ATP-dependent drug efflux pump P-glycoprotein (P-gp) affects the absorption and disposition of many compounds. P-gp may also play role in clinically significant drug-drug interactions. Therefore, it is important to find potential substrates or inhibitors of P-gp early in the drug discovery process. To identify compounds that interact with this transporter, several P-gp assays were validated and compared by testing a set of 28 reference compounds, including inhibitors of cytochrome P450 3A4 (CYP3A4). The assays included in silico predictions, inhibition assays (based on cellular uptake of rhodamine-123 or calcein AM), and functional assays (ATPase activity assay and transcellular transport assay, the latter for a subset of compounds). In addition, species differences were studied in an indirect fluorescence indicator screening assay and test systems expressing porcine, mouse, or human P-gp. Our results suggest that several P-gp assays should be used in combination to classify compounds as substrates or inhibitors of P-gp. Recommendations are given on screening strategies which can be applied to different phases of the drug discovery and development process.
|
Antisecretory activity evaluated by the inhibition of 14C -AP uptake in isolated rabbit parietal cells stimulated by exogenous histamine
|
Oryctolagus cuniculus
|
820.0
nM
|
|
Journal : J. Med. Chem.
Title : Synthesis of (aryloxy)alkylamines. 1. Novel antisecretory agents with H+K+-ATPase inhibitory activity.
Year : 1988
Volume : 31
Issue : 9
First Page : 1778
Last Page : 1785
Authors : Sanfilippo PJ, Urbanski M, Press JB, Hajos ZG, Shriver DA, Scott CK.
Abstract : A series of heterocyclic (aryloxy)alkylamines of structures II and III were prepared and found to possess gastric antisecretory activity. Of the variety of substituted thiazoles, benzoxazoles, and benzothiazoles prepared, thiazole 18, benzoxazole 32, and benzothiazole 47 exhibited gastric antisecretory potency comparable to that of ranitidine in vivo in the pylorous ligated rat model. In an isolated rabbit parietal system, the series of thiazoles, benzoxazoles, and benzothiazoles also demonstrated similar potency to that of ranitidine toward the inhibition of both histamine-stimulated and dcAMP-stimulated uptake of amino[14C]pyrine. These compounds inhibited the H+K+-sensitive ATPase enzyme in isolated gastric microsomes. A direct correlation existed between inhibition of 14C uptake, in vivo antisecretory activity, and inhibition of the H+K+-ATPase enzyme. The more potent antisecretory compounds 18, 32, and 47 were also the more potent enzyme inhibitors. These data suggest that the mechanism responsible for the observed in vitro and in vivo gastric antisecretory activity, in these series of compounds, is a consequence of the inhibition of the H+K+-sensitive ATPase enzyme.
|
In vivo gastric antisecretory activity in acute fistula rats (12.5 mg/kg, id)
|
Rattus norvegicus
|
51.4
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and antiulcer activity of N-substituted N'-[3-[3-(piperidinomethyl)phenoxy]propyl]ureas: histamine H2-receptor antagonists with a potent mucosal protective activity.
Year : 1992
Volume : 35
Issue : 13
First Page : 2446
Last Page : 2451
Authors : Miyashita M, Matsumoto T, Matsukubo H, Iinuma F, Taga F, Sekiguchi H, Hamada K, Okamura K, Nishino K.
Abstract : As an aim toward developing new antiulcer agents, new N-substituted N'-[3-[3-(piperidinomethyl)phenoxy]propyl]ureas were synthesized and evaluated for histamine H2-receptor antagonistic, gastric antisecretory, and gastric mucosal protective activities. A QSAR study showed that the most favorable N-substituents were electron-donating straight-chain alkyl groups of short length such as ethyl group from the viewpoint of dual action, i.e., gastric antisecretory and mucosal protective actions. Among the ureas studied, compounds 4, 5, and 8-10 were selected as candidates for further study.
|
Compound was measured for percentage inhibition of aspirin-induced ulcers at 10 mg/kg after po administration
|
Rattus norvegicus
|
67.0
%
|
|
Journal : J. Med. Chem.
Title : Gastric antisecretory agents. 1. Antisecretory and antiulcer activity of 5H-[1]benzopyrano[2,3-b]pyridin-5-ylureas and 5H-[1]benzothiopyrano[2,3-b]pyridin-5-ylureas.
Year : 1981
Volume : 24
Issue : 8
First Page : 927
Last Page : 932
Authors : Bristol JA, Gold EH, Lovey RG, Long JF.
|
Percent inhibition of gastric antisecretory activity in the 4 hr pylorus-ligated rat to that of control at a dose of 100 mg/kg
|
Rattus norvegicus
|
80.6
%
|
|
Journal : J. Med. Chem.
Title : Pyridazinones. 3. Synthesis, antisecretory, and antiulcer activities of 2-cyanoguanidine derivatives.
Year : 1983
Volume : 26
Issue : 8
First Page : 1144
Last Page : 1149
Authors : Yamada T, Shimamura H, Tsukamoto Y, Yamaguchi A, Ohki M.
Abstract : 3(2H)-Pyridazinone derivatives having a 2-cyanoguanidine moiety, as well as a sulfur or an oxygen atom in the alkylene side chain, were synthesized and evaluated for gastric antisecretory and antiulcer activities. The key intermediates, free amines having a thioether linkage, were synthesized by the reaction of 2-(omega-chloroalkyl) derivatives with cysteamine, while other intermediates having an ether linkage were synthesized from 2-(omega-chloroalkyl)oxymethyl derivatives. These free amines were converted via the 3-cyano-2-methyl-1-isothiourea derivatives into the desired 2-cyano-3-substituted-1-guanidine derivatives. All compounds synthesized were evaluated for gastric antisecretory activity in the pylorus-ligated rat by the method of Shay, and selected compounds were evaluated in the stress-induced ulcer test in rat. Structure-activity relationships are discussed. The molecular features for the best activities are a phenyl group in the C-6 position of the 3(2H)-pyridazinone ring, a four-atom chain length between the 3(2H)-pyridazinone ring and the 2-cyanoguanidine moiety, and a thioether rather than an ether linkage. Among them, compound 14, 2-[[[2-(2-cyano-3-methyl-1-guanidino)ethyl]thio]methyl]-6-phenyl-3 (2H)-pyridazinone, had the most potent antisecretory and antiulcer activities. These compounds are neither histamine H2 receptor inhibitors nor anticholinergic agents.
|
Inhibition of histamine stimulated gastric acid secretion in lumen perfused stomach of anesthetized rats (1 mg/kg iv)
|
Rattus norvegicus
|
53.0
%
|
|
Journal : J. Med. Chem.
Title : Anti-Helicobacter pylori agents. 4. 2-(Substituted guanidino)-4-phenylthiazoles and some structurally rigid derivatives.
Year : 2000
Volume : 43
Issue : 17
First Page : 3315
Last Page : 3321
Authors : Katsura Y, Tomishi T, Inoue Y, Sakane K, Matsumoto Y, Morinaga C, Ishikawa H, Takasugi H.
Abstract : In order to find a new class of anti-Helicobacter pylori (H. pylori) agents, a series of 4-[(3-acetamido)phenyl]-2-(substituted guanidino)thiazoles and some structurally rigid analoges were synthesized and evaluated for antimicrobial activity against H. pylori. Among the compounds obtained, high anti-H. pyrori activities were observed in benzyl derivative 34 (MIC = 0.025 microg/mL) and phenethyl derivatives 35 and 36 (MIC = 0.037 microg/mL and 0.017 microg/mL). Though alkyl derivatives generally showed lower activity, the 2-methoxyethyl derivative 28 preserved significant activity (MIC = 0.32 microg/mL) and also exhibited more potent gastric antisecretory activity than ranitidine. Structural restriction by bridging between the thiazole and the phenyl rings with an alkyl chain did not improve the activity in this series.
|
Inhibition of aspirin induced gastric lesions in rats after peroral dose of 32 mg/kg
|
Rattus norvegicus
|
33.0
%
|
|
Journal : J. Med. Chem.
Title : Studies on antiulcer drugs. 7. 2-Guanidino-4-pyridylthiazoles as histamine H2-receptor antagonists with potent gastroprotective effects against nonsteroidal antiinflammatory drug-induced injury.
Year : 1994
Volume : 37
Issue : 1
First Page : 57
Last Page : 66
Authors : Katsura Y, Inoue Y, Tomishi T, Ishikawa H, Takasugi H.
Abstract : A series of 2-guanidino-4-pyridylthiazole derivatives were synthesized and evaluated for anti-aspirin-ulcer, gastric antisecretory, and histamine-H2-receptor-antagonist activities. Several compounds showed superior anti-aspirin-ulcer activity to that of clinically used H2-antagonists in the rat. Among them, 4-[6-(acetamidomethyl)pyridin-2-yl]-2-guanidinothiazole (8) demonstrated potent inhibitory activities against gastric lesions caused by two kinds of nonsteroidal antiinflammatory drugs, aspirin and indomethacin, respectively, in addition to strong antisecretory activity. Compound 8 possessed a preventable ability for the aspirin-induced reduction of the gastric mucosal blood flow at an intragastric administration of 32 mg/kg in the rat. On the other hand, famotidine (32 mg/kg) exhibited no significant effect and ranitidine (100 mg/kg) aggravated the blood flow in this system.
|
Inhibition of histamine stimulated gastric acid secretion in lumen perfused anaesthetized rats after 1 mg/kg intravenous dose
|
Rattus norvegicus
|
53.0
%
|
|
Journal : J. Med. Chem.
Title : Studies on antiulcer drugs. 7. 2-Guanidino-4-pyridylthiazoles as histamine H2-receptor antagonists with potent gastroprotective effects against nonsteroidal antiinflammatory drug-induced injury.
Year : 1994
Volume : 37
Issue : 1
First Page : 57
Last Page : 66
Authors : Katsura Y, Inoue Y, Tomishi T, Ishikawa H, Takasugi H.
Abstract : A series of 2-guanidino-4-pyridylthiazole derivatives were synthesized and evaluated for anti-aspirin-ulcer, gastric antisecretory, and histamine-H2-receptor-antagonist activities. Several compounds showed superior anti-aspirin-ulcer activity to that of clinically used H2-antagonists in the rat. Among them, 4-[6-(acetamidomethyl)pyridin-2-yl]-2-guanidinothiazole (8) demonstrated potent inhibitory activities against gastric lesions caused by two kinds of nonsteroidal antiinflammatory drugs, aspirin and indomethacin, respectively, in addition to strong antisecretory activity. Compound 8 possessed a preventable ability for the aspirin-induced reduction of the gastric mucosal blood flow at an intragastric administration of 32 mg/kg in the rat. On the other hand, famotidine (32 mg/kg) exhibited no significant effect and ranitidine (100 mg/kg) aggravated the blood flow in this system.
|
In Vivo gastric Mucosal protective activity against gastric mucosal lesions induced by 0.6 N HCl in rats. (200 mg/kg, po)
|
Rattus norvegicus
|
-42.2
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and antiulcer activity of N-substituted N'-[3-[3-(piperidinomethyl)phenoxy]propyl]ureas: histamine H2-receptor antagonists with a potent mucosal protective activity.
Year : 1992
Volume : 35
Issue : 13
First Page : 2446
Last Page : 2451
Authors : Miyashita M, Matsumoto T, Matsukubo H, Iinuma F, Taga F, Sekiguchi H, Hamada K, Okamura K, Nishino K.
Abstract : As an aim toward developing new antiulcer agents, new N-substituted N'-[3-[3-(piperidinomethyl)phenoxy]propyl]ureas were synthesized and evaluated for histamine H2-receptor antagonistic, gastric antisecretory, and gastric mucosal protective activities. A QSAR study showed that the most favorable N-substituents were electron-donating straight-chain alkyl groups of short length such as ethyl group from the viewpoint of dual action, i.e., gastric antisecretory and mucosal protective actions. Among the ureas studied, compounds 4, 5, and 8-10 were selected as candidates for further study.
|
Gastric antisecretory activity at the dose of 100 mg/kg in pylorus lygated rats
|
Rattus norvegicus
|
80.6
%
|
|
Journal : J. Med. Chem.
Title : Pyridazinones. 2. Synthesis and antisecretory and antiulcer activities of thiourea and 2-cyanoguanidine derivatives.
Year : 1983
Volume : 26
Issue : 3
First Page : 373
Last Page : 381
Authors : Yamada T, Nobuhara Y, Shimamura H, Tsukamoto Y, Yoshihara K, Yamaguchi A, Ohki M.
Abstract : In an effort to develop new types of antiulcer agents, we synthesized a series of novel 2-[omega-(thioureido)alkyl]- and 2-[omega-(cyanoguanidino)alkyl]-3(2H)-pyridazinone derivatives. All target compounds were evaluated for gastric antisecretory activity in the pylorus-lygated rat by the method of Shay, and selected compounds were evaluated in the stress-induced ulcer test in rats. Structure-activity relationships were established. Two series of the compounds had significant activity in antisecretory and/or antiulcer tests. The molecular features essential for the activities are a thiourea group or a 2-cyanoguanidine group, a phenyl group in the C-6 position of the 3(2H)-pyridazinone ring, a four-carbon chain length between the 3(2H)-pyridazinone ring and the functional group, and a methyl group at the N-3 position of the functional group. Among them, the three thiourea derivatives (24, 26, and 38) and the six 2-cyanoguanidine derivatives (61, 62, 65, 75, 85, and 86) had the most potent antisecretory and/or antiulcer activities. These compounds are not histamine H2-receptor antagonists.
|
Inhibition of histamine-stimulated gastric acid secretion in lumen-perfused stomach of the anaesthetized rats when administered 1 mg/kg intravenously
|
Rattus norvegicus
|
22.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Anti-Helicobacter pylori agents. 2. Structure activity relationships in a new series of 2-alkylguanidino-4-furylthiazoles.
Year : 1998
Volume : 8
Issue : 11
First Page : 1307
Last Page : 1312
Authors : Katsura Y, Nishino S, Tomishi T, Sakane K, Matsumoto Y, Ishikawa H, Takasugi H.
Abstract : SAR for antimicrobial activity against H. pylori was investigated in a new series of 2-alkylguanidino-4-furylthiazoles. Of the compounds obtained, cyclohexylmethyl and ethoxyethyl derivatives were identified as a novel class of anti-H. pylori agents which possessed potent and selective antimicrobial activity against H. pylori. These compounds also showed gastric antisecretory activity.
|
Inhibition of stress-induced ulcer formation in rats by 10 mg/kg p.o. administration.
|
Rattus norvegicus
|
33.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and antiulcer activity of 5,11-dihydro[1]benzoxepino[3,4-b]pyridines.
Year : 1988
Volume : 31
Issue : 4
First Page : 779
Last Page : 785
Authors : Kumazawa T, Harakawa H, Obase H, Oiji Y, Tanaka H, Shuto K, Ishii A, Oka T, Nakamizo N.
Abstract : A series of substituted 5,11-dihydro[1]benzoxepino[3,4-b]pyridines was synthesized and evaluated for antiulcer activity in water immersion/restrained stress ulcer assay in rats. Structure-activity relationships are described. Most of the tested compounds exhibited low affinity to the muscarinic acetylcholine receptor. The molecular features for the best activities are the 2-(diethylamino)ethylenediamine group at the 5-position of the oxepin ring and an oxepin skeleton rather than a thiepin or a pyran skeleton. Methyl and chlorine substitution on the benzene ring reduced the activity. Compound 11, 5-[[2-(diethylamino)ethyl]amino]-5,11-dihydro[1]benzoxepino [3,4-b]pyridine trihydrochloride was selected for further evaluation. Synthesis and antiulcer activity of optically active 11 is described. There were no statistically significant differences between (+)-, (-)-, and (+/-)-11. Compound 11 showed weak antisecretory activity in pylorus-ligated rats. It is now under clinical evaluation as KW 5805.
|
The antiulcer activity against stress-induced ulcer in rats by 30 mg/kg peroral administration.
|
Rattus norvegicus
|
39.0
%
|
|
Journal : J. Med. Chem.
Title : Synthesis and antiulcer activity of 5,11-dihydro[1]benzoxepino[3,4-b]pyridines.
Year : 1988
Volume : 31
Issue : 4
First Page : 779
Last Page : 785
Authors : Kumazawa T, Harakawa H, Obase H, Oiji Y, Tanaka H, Shuto K, Ishii A, Oka T, Nakamizo N.
Abstract : A series of substituted 5,11-dihydro[1]benzoxepino[3,4-b]pyridines was synthesized and evaluated for antiulcer activity in water immersion/restrained stress ulcer assay in rats. Structure-activity relationships are described. Most of the tested compounds exhibited low affinity to the muscarinic acetylcholine receptor. The molecular features for the best activities are the 2-(diethylamino)ethylenediamine group at the 5-position of the oxepin ring and an oxepin skeleton rather than a thiepin or a pyran skeleton. Methyl and chlorine substitution on the benzene ring reduced the activity. Compound 11, 5-[[2-(diethylamino)ethyl]amino]-5,11-dihydro[1]benzoxepino [3,4-b]pyridine trihydrochloride was selected for further evaluation. Synthesis and antiulcer activity of optically active 11 is described. There were no statistically significant differences between (+)-, (-)-, and (+/-)-11. Compound 11 showed weak antisecretory activity in pylorus-ligated rats. It is now under clinical evaluation as KW 5805.
|
inhibition of histamine stimulated gastric secretion in lumen perfused stomach of anesthetized rats at 1 mg/kg intravenously
|
Rattus norvegicus
|
53.0
%
|
|
Journal : J. Med. Chem.
Title : Anti-Helicobacter pylori agents. 1. 2-(Alkylguanidino)-4-furylthiazoles and related compounds.
Year : 1997
Volume : 40
Issue : 16
First Page : 2462
Last Page : 2465
Authors : Katsura Y, Tomishi T, Inoue Y, Sakane K, Matsumoto Y, Ishikawa H, Takasugi H.
Abstract : A series of 2-(alkylguanidino)-4-[5-(acetamidomethyl)furan-2-yl]thiazoles and related compounds were synthesized and evaluated for antimicrobial activity against Helicobacter pylori, inhibitory effect on gastric acid secretion, and histamine H2-receptor antagonist activity. Introduction of alkyl substituents on the guanidino moiety resulted in a significant increase in antimicrobial activity, which was associated with the alkyl chain length. Of the compounds obtained, the n-hexylguanidino derivative 13 demonstrated a 250-fold improvement in activity (MIC = 0.11 micrograms/mL) over the unsubstituted guanidino derivative 7. Alkyl-substituted guanidino derivatives also displayed gastric antisecretion and H2-antagonist activities. However, a simple correlation between the alkyl chain length and the activities was not found in these assays. Replacement of the guanidine with other bioisosteric groups (thiourea, urea, or (dimethylamino)methyl) resulted in loss of all activities tested. Thus the guanidino moiety was found to be essential for activity in this series of compounds.
|
Inhibition of histamine stimulated gastric acid secretion in lumen perfused stomach of anesthetized rats at 1 mg/kg i.v. dose
|
Rattus norvegicus
|
53.0
%
|
|
Journal : J. Med. Chem.
Title : Anti-Helicobacter pylori agents. 3. 2-[(Arylalkyl)guanidino]-4-furylthiazoles.
Year : 1999
Volume : 42
Issue : 15
First Page : 2920
Last Page : 2926
Authors : Katsura Y, Nishino S, Ohno M, Sakane K, Matsumoto Y, Morinaga C, Ishikawa H, Takasugi H.
Abstract : A series of 2-[(arylalkyl)guanidino]-4-[(5-acetamidomethyl)furan-2-yl]thiazole s and some 4-acetamidomethyl positional isomers were synthesized and evaluated for antimicrobial activity against Helicobacter pylori. Among the compounds that had potent antimicrobial activity (MIC < 0. 1 microgram/mL), compounds 31 and 36 additionally possessed H2 antagonist and gastric antisecretory activities. Though compound 51, an analogue incorporating a methyl group onto the furan nucleus of 36, and compound 54, a positional isomer of 51, also showed potent anti-H. pylori activity, the H2 antagonism profile was eliminated from these compounds. Thus, two types of potent anti-H. pylori agents could be derived from the same scaffold.
|
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
|
0.0
%
|
|
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.
|
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 100 uM
|
Cavia porcellus
|
4.1
%
|
|
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.
|
Inhibition of histamine-stimulated chronotropic response in isolated guinea pig right atrium at 1*10e-6 g/mL
|
Cavia porcellus
|
43.0
%
|
|
Journal : J. Med. Chem.
Title : Anti-Helicobacter pylori agents. 5. 2-(Substituted guanidino)-4-arylthiazoles and aryloxazole analogues.
Year : 2002
Volume : 45
Issue : 1
First Page : 143
Last Page : 150
Authors : Katsura Y, Nishino S, Inoue Y, Sakane K, Matsumoto Y, Morinaga C, Ishikawa H, Takasugi H.
Abstract : To extend the SAR study of guanidinothiazoles as a structurally novel class of anti-H. pylori agents, a series of 2-(substituted guanidino)-4-arylthiazoles and some 4-aryloxazole analogues were synthesized and evaluated for antimicrobial activity against H. pylori. Some of them were also subjected to H2 antagonist and gastric antisecretory assays. Several arylthiazoles were identified as potent anti-H. pylori agents, and of these, thienylthiazole derivative 44 exhibited the strongest activity (MIC = 0.0065 microg/mL) among the compounds obtained in our guanidinothiazole studies. Although 44 was void of H2 antagonist activity, pyridylthiazole derivative 39 had both potent anti-H. pylori and H2 antagonist activities. Thiazolylthiazole derivative 46 also showed potent anti-H. pylori activity, but the H2 antagonist activity was weak. On the other hand, no attractive activities were found in pyrimidyl, oxazolyl, isoxazolyl, imidazolyl, and oxadiazolylthiazole derivatives. The anti-H. pylori activity of the aryloxazole analogues was weaker than those of the corresponding arylthiazole derivatives, though they had potent H2 antagonist activity.
|
Inhibition of histamine-stimulated gastric acid secretion in lumen-perfused stomach of anesthetized rats after 1 mg/kg iv administration
|
Rattus norvegicus
|
53.0
%
|
|
Journal : J. Med. Chem.
Title : Anti-Helicobacter pylori agents. 5. 2-(Substituted guanidino)-4-arylthiazoles and aryloxazole analogues.
Year : 2002
Volume : 45
Issue : 1
First Page : 143
Last Page : 150
Authors : Katsura Y, Nishino S, Inoue Y, Sakane K, Matsumoto Y, Morinaga C, Ishikawa H, Takasugi H.
Abstract : To extend the SAR study of guanidinothiazoles as a structurally novel class of anti-H. pylori agents, a series of 2-(substituted guanidino)-4-arylthiazoles and some 4-aryloxazole analogues were synthesized and evaluated for antimicrobial activity against H. pylori. Some of them were also subjected to H2 antagonist and gastric antisecretory assays. Several arylthiazoles were identified as potent anti-H. pylori agents, and of these, thienylthiazole derivative 44 exhibited the strongest activity (MIC = 0.0065 microg/mL) among the compounds obtained in our guanidinothiazole studies. Although 44 was void of H2 antagonist activity, pyridylthiazole derivative 39 had both potent anti-H. pylori and H2 antagonist activities. Thiazolylthiazole derivative 46 also showed potent anti-H. pylori activity, but the H2 antagonist activity was weak. On the other hand, no attractive activities were found in pyrimidyl, oxazolyl, isoxazolyl, imidazolyl, and oxadiazolylthiazole derivatives. The anti-H. pylori activity of the aryloxazole analogues was weaker than those of the corresponding arylthiazole derivatives, though they had potent H2 antagonist activity.
|
Inhibition of histamine H2 receptor
|
None
|
781.0
nM
|
|
Journal : J. Med. Chem.
Title : Identification of a potent, selective, and orally active leukotriene a4 hydrolase inhibitor with anti-inflammatory activity.
Year : 2008
Volume : 51
Issue : 14
First Page : 4150
Last Page : 4169
Authors : Grice CA, Tays KL, Savall BM, Wei J, Butler CR, Axe FU, Bembenek SD, Fourie AM, Dunford PJ, Lundeen K, Coles F, Xue X, Riley JP, Williams KN, Karlsson L, Edwards JP.
Abstract : LTA 4H is a ubiquitously distributed 69 kDa zinc-containing cytosolic enzyme with both hydrolase and aminopeptidase activity. As a hydrolase, LTA 4H stereospecifically catalyzes the transformation of the unstable epoxide LTA 4 to the diol LTB 4, a potent chemoattractant and activator of neutrophils and a chemoattractant of eosinophils, macrophages, mast cells, and T cells. Inhibiting the formation of LTB 4 is expected to be beneficial in the treatment of inflammatory diseases such as inflammatory bowel disease (IBD), asthma, and atherosclerosis. We developed a pharmacophore model using a known inhibitor manually docked into the active site of LTA 4H to identify a subset of compounds for screening. From this work we identified a series of benzoxazole, benzthiazole, and benzimidazole inhibitors. SAR studies resulted in the identification of several potent inhibitors with an appropriate cross-reactivity profile and excellent PK/PD properties. Our efforts focused on further profiling JNJ 27265732, which showed encouraging efficacy in a disease model relevant to IBD.
|
Displacement of radiolabeled cimetidine from human histamine H2 receptor
|
Homo sapiens
|
180.0
nM
|
|
Displacement of radiolabeled cimetidine from human histamine H2 receptor
|
Homo sapiens
|
170.0
nM
|
|
Journal : J. Med. Chem.
Title : cis-4-(Piperazin-1-yl)-5,6,7a,8,9,10,11,11a-octahydrobenzofuro[2,3-h]quinazolin-2-amine (A-987306), a new histamine H4R antagonist that blocks pain responses against carrageenan-induced hyperalgesia.
Year : 2008
Volume : 51
Issue : 22
First Page : 7094
Last Page : 7098
Authors : Liu H, Altenbach RJ, Carr TL, Chandran P, Hsieh GC, Lewis LG, Manelli AM, Milicic I, Marsh KC, Miller TR, Strakhova MI, Vortherms TA, Wakefield BD, Wetter JM, Witte DG, Honore P, Esbenshade TA, Brioni JD, Cowart MD.
Abstract : cis-4-(Piperazin-1-yl)-5,6,7a,8,9,10,11,11a-octahydrobenzofuro[2,3-h]quinazolin-2-amine, 4 (A-987306) is a new histamine H(4) antagonist. The compound is potent in H(4) receptor binding assays (rat H(4), K(i) = 3.4 nM, human H(4) K(i) = 5.8 nM) and demonstrated potent functional antagonism in vitro at human, rat, and mouse H(4) receptors in cell-based FLIPR assays. Compound 4 also demonstrated H(4) antagonism in vivo in mice, blocking H(4)-agonist induced scratch responses, and showed anti-inflammatory activity in mice in a peritonitis model. Most interesting was the high potency and efficacy of this compound in blocking pain responses, where it showed an ED(50) of 42 mumol/kg (ip) in a rat post-carrageenan thermal hyperalgesia model of inflammatory pain.
|
Inhibition of 4-(4-(dimethylamino)styryl)-N-methylpyridinium uptake at human OCT1 expressed in HEK293 cells at 100 uM by confocal microscopy
|
Homo sapiens
|
8.1
%
|
|
Journal : J. Med. Chem.
Title : Structural requirements for drug inhibition of the liver specific human organic cation transport protein 1.
Year : 2008
Volume : 51
Issue : 19
First Page : 5932
Last Page : 5942
Authors : Ahlin G, Karlsson J, Pedersen JM, Gustavsson L, Larsson R, Matsson P, Norinder U, Bergström CA, Artursson P.
Abstract : The liver-specific organic cation transport protein (OCT1; SLC22A1) transports several cationic drugs including the antidiabetic drug metformin and the anticancer agents oxaliplatin and imatinib. In this study, we explored the chemical space of registered oral drugs with the aim of studying the inhibition pattern of OCT1 and of developing predictive computational models of OCT1 inhibition. In total, 191 structurally diverse compounds were examined in HEK293-OCT1 cells. The assay identified 47 novel inhibitors and confirmed 15 previously known inhibitors. The enrichment of OCT1 inhibitors was seen in several drug classes including antidepressants. High lipophilicity and a positive net charge were found to be the key physicochemical properties for OCT1 inhibition, whereas a high molecular dipole moment and many hydrogen bonds were negatively correlated to OCT1 inhibition. The data were used to generate OPLS-DA models for OCT1 inhibitors; the final model correctly predicted 82% of the inhibitors and 88% of the noninhibitors of the test set.
|
Inhibition of water-immersion stress-induced ulcer formation in rat at 30 mg/kg
|
Rattus norvegicus
|
74.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Possible involvement of radical intermediates in the inhibition of cysteine proteases by allenyl esters and amides.
Year : 2008
Volume : 18
Issue : 23
First Page : 6202
Last Page : 6205
Authors : Takeuchi Y, Fujiwara T, Shimone Y, Miyataka H, Satoh T, Kirk KL, Hori H.
Abstract : In order to investigate crystallographically the mechanism of inhibition of cysteine protease by alpha-methyl-gamma,gamma-diphenylallenecarboxylic acid ethyl ester 3, a cysteine protease inhibitor having in vivo stability, we synthesized N-(alpha-methyl-gamma,gamma-diphenylallenecarbonyl)-L-phenylalanine ethyl ester 4. Reaction of 4 with thiophenol, the SH group of which has similar pK(a) value to that of cysteine protease, produced oxygen-mediated radical adducts 6 and 7 in ambient air but did not proceed under oxygen-free conditions. Catalytic activities of two thiol enzymes including cathepsin B were also lowered in the absence of oxygen. These results suggest that cysteine protease can act through an oxygen-dependent radical mechanism.
|
TP_TRANSPORTER: inhibition of MPP+ uptake (MPP+: 1 uM) in Xenopus laevis oocytes
|
Xenopus laevis
|
590.0
nM
|
|
Journal : Biochem. Biophys. Res. Commun.
Title : Functional characterization of mouse cation transporter mOCT2 compared with mOCT1.
Year : 2002
Volume : 296
Issue : 1
First Page : 644
Last Page : 650
Authors : Kakehi M, Koyabu N, Nakamura T, Uchiumi T, Kuwano M, Ohtani H, Sawada Y.
Abstract : We characterized the function of mouse organic cation transporter OCT2 (TC 2.A.19.1.5) in comparison with that of OCT1 (TC 2.A.19.1.1). Uptake of [(3)H]1-methyl-4-phenylpyridinium ([(3)H]MPP(+)) by Xenopus laevis oocytes injected with mOCT1 (Slc22a1) or mOCT2 (Slc22a2) cRNA was attenuated by an increase of extracellular K(+) concentration and under acidic extracellular conditions. The uptakes of [(3)H]MPP(+) via mOCT1 and mOCT2 were saturable, with similar Michaelis constants (K(t)) of 10 and 24 microM, respectively. mOCT2 also mediated the uptake of [(14)C]tetraethylammonium with a K(t) value of 36 microM, which is similar to that of mOCT1. Quinine, tetraethylammonium, cimetidine, procainamide, choline, and N(')-methylnicotinamide inhibited the uptake of [(3)H]MPP(+) via mOCT1, as well as via mOCT2, and the inhibitory potencies for mOCT1 were comparable to but slightly higher than those for mOCT2. Thus, although the transport properties of mOCT2 are similar to those of mOCT1 in respect to the membrane-potential dependency, pH-sensitivity, and affinities for MPP(+) and tetraethylammonium, several organic cations had weaker inhibitory effects on [(3)H]MPP(+) uptake by mOCT2 than by mOCT1.
|
TP_TRANSPORTER: inhibition of TEA uptake (TEA: 20 uM, Cimetidine: 5000 uM) in OCT3-expressing HRPE cells
|
None
|
90.0
%
|
|
Journal : Am. J. Physiol. Renal Physiol.
Title : Structure, function, and regional distribution of the organic cation transporter OCT3 in the kidney.
Year : 2000
Volume : 279
Issue : 1
First Page : F449
Last Page : F458
Authors : Wu X, Huang W, Ganapathy ME, Wang H, Kekuda R, Conway SJ, Leibach FH, Ganapathy V.
Abstract : We examined in this study the expression of the potential-sensitive organic cation transporter OCT3 in the kidney. A functionally active OCT3 was cloned from a mouse kidney cDNA library. The cloned transporter was found to be capable of mediating potential-dependent transport of a variety of organic cations including tetraethylammonium. This function was confirmed in two different heterologous expression systems involving mammalian cells and Xenopus laevis oocytes. We have also isolated the mouse OCT3 gene and deduced its structure and organization. The OCT3 gene consists of 11 exons and 10 introns. In situ hybridization studies in the mouse kidney have shown that OCT3 mRNA is expressed primarily in the cortex. The expression is evident in the proximal and distal convoluted tubules. The expression of OCT3 in human kidney was confirmed by RT-PCR. We have also cloned OCT3 from human placenta and human kidney. Human OCT3 exhibits 86% identity with mouse OCT3 in amino acid sequence. Human OCT3 was found to transport tetraethylammonium and a variety of other organic cations. The transport process was electrogenic. We conclude that OCT3 is expressed in mammalian kidney and that it plays an important role in the renal clearance of cationic drugs.
|
Inhibition of human liver OATP1B1 expressed in HEK293 Flp-In cells assessed as reduction in E17-betaG uptake at 20 uM by scintillation counting
|
Homo sapiens
|
40.3
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human liver OATP1B3 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E17-betaG uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
24.8
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
Inhibition of human liver OATP2B1 expressed in HEK293 Flp-In cells assessed as reduction in [3H]E3S uptake at 20 uM incubated for 5 mins by scintillation counting
|
Homo sapiens
|
-6.2
%
|
|
Journal : J. Med. Chem.
Title : Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.
Year : 2012
Volume : 55
Issue : 10
First Page : 4740
Last Page : 4763
Authors : Karlgren M, Vildhede A, Norinder U, Wisniewski JR, Kimoto E, Lai Y, Haglund U, Artursson P.
Abstract : The hepatic organic anion transporting polypeptides (OATPs) influence the pharmacokinetics of several drug classes and are involved in many clinical drug-drug interactions. Predicting potential interactions with OATPs is, therefore, of value. Here, we developed in vitro and in silico models for identification and prediction of specific and general inhibitors of OATP1B1, OATP1B3, and OATP2B1. The maximal transport activity (MTA) of each OATP in human liver was predicted from transport kinetics and protein quantification. We then used MTA to predict the effects of a subset of inhibitors on atorvastatin uptake in vivo. Using a data set of 225 drug-like compounds, 91 OATP inhibitors were identified. In silico models indicated that lipophilicity and polar surface area are key molecular features of OATP inhibition. MTA predictions identified OATP1B1 and OATP1B3 as major determinants of atorvastatin uptake in vivo. The relative contributions to overall hepatic uptake varied with isoform specificities of the inhibitors.
|
inhibition of human PAD4 preincubated at 10 uM for 15 mins before substrate addition measured after 20 mins by spectrophotometry
|
Homo sapiens
|
1.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel small molecule protein arginine deiminase 4 (PAD4) inhibitors.
Year : 2013
Volume : 23
Issue : 3
First Page : 715
Last Page : 719
Authors : Bozdag M, Dreker T, Henry C, Tosco P, Vallaro M, Fruttero R, Scozzafava A, Carta F, Supuran CT.
Abstract : Protein arginin deaminase 4 (PAD4) is a calcium dependent enzyme which catalyses the conversion of peptidyl-arginine into peptidyl-citrulline and is implicated in several diseases such as rheumatoid arthritis (RA) and cancer. Herein we report the discovery of novel small-molecule, non peptidic PAD4 inhibitors incorporating primary/secondary guanidine moieties.
|
inhibition of human PAD4 preincubated at 1 uM for 15 mins before substrate addition measured after 20 mins by spectrophotometry
|
Homo sapiens
|
0.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel small molecule protein arginine deiminase 4 (PAD4) inhibitors.
Year : 2013
Volume : 23
Issue : 3
First Page : 715
Last Page : 719
Authors : Bozdag M, Dreker T, Henry C, Tosco P, Vallaro M, Fruttero R, Scozzafava A, Carta F, Supuran CT.
Abstract : Protein arginin deaminase 4 (PAD4) is a calcium dependent enzyme which catalyses the conversion of peptidyl-arginine into peptidyl-citrulline and is implicated in several diseases such as rheumatoid arthritis (RA) and cancer. Herein we report the discovery of novel small-molecule, non peptidic PAD4 inhibitors incorporating primary/secondary guanidine moieties.
|
Binding affinity to human histamine H2 receptor by radioligand displacement assay
|
Homo sapiens
|
270.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and biological evaluation of 2-(5-methyl-4-phenyl-2-oxopyrrolidin-1-yl)-acetamide stereoisomers as novel positive allosteric modulators of sigma-1 receptor.
Year : 2013
Volume : 21
Issue : 10
First Page : 2764
Last Page : 2771
Authors : Veinberg G, Vorona M, Zvejniece L, Vilskersts R, Vavers E, Liepinsh E, Kazoka H, Belyakov S, Mishnev A, Kuznecovs J, Vikainis S, Orlova N, Lebedev A, Ponomaryov Y, Dambrova M.
Abstract : Novel positive allosteric modulators of sigma-1 receptor represented by 2-(5-methyl-4-phenyl-2-oxopyrrolidin-1-yl)-acetamide enantiomers were synthesised using an asymmetric Michael addition of 2-nitroprop-1-enylbenzene to diethyl malonate. Following the chromatographic separation of the methyl erythro- and threo-4-nitro-3R- and 3S-phenylpentanoate diastereoisomers, target compounds were obtained by their reductive cyclisation into 5-methyl-4-phenylpyrrolidin-2-one enantiomers and the attachment of the acetamide group to the heterocyclic nitrogen. Experiments with electrically stimulated rat vas deference contractions induced by the PRE-084, an agonist of sigma-1 receptor, showed that (4R,5S)- and (4R,5R)-2-(5-methyl-4-phenyl-2-oxopyrrolidin-1-yl)-acetamides with an R-configuration at the C-4 chiral centre in the 2-pyrrolidone ring were more effective positive allosteric modulators of sigma-1 receptor than were their optical antipodes.
|
Binding affinity to human histamine H2 receptor by radioligand displacement assay
|
Homo sapiens
|
140.0
nM
|
|
Binding affinity to human histamine H2 receptor by radioligand displacement assay
|
Homo sapiens
|
140.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and structure-activity relationship studies in serotonin 5-HT(1A) receptor agonists based on fused pyrrolidone scaffolds.
Year : 2013
Volume : 63
First Page : 85
Last Page : 94
Authors : Cappelli A, Manini M, Valenti S, Castriconi F, Giuliani G, Anzini M, Brogi S, Butini S, Gemma S, Campiani G, Giorgi G, Mennuni L, Lanza M, Giordani A, Caselli G, Letari O, Makovec F.
Abstract : A new class of serotonin 5-HT1A receptor ligands related to NAN-190, buspirone and aripiprazole has been designed using our potent 5-HT3 receptor ligands as templates. The designed pyrrolidone derivatives 10a-n were prepared by means of the straightforward chemistry consisting in the reaction of the appropriate γ-haloester derivatives with the suitable arylpiperazinylalkylamines. The nanomolar 5-HT1A receptor affinity and the agonist-like profile shown by fused pyrrolidone derivatives 10k,m stimulated the rationalization of the interaction with an homology model of the 5-HT1A receptor and the evaluation of their selectivity profiles and the pharmacokinetic properties. Interestingly, the results of the profiling assays suggested for close congeners 10k,m a significantly divergent binding pattern with compound 10m showing an appreciable selectivity for 5-HT1AR.
|
Gastroprotective activity in Wistar rat assessed as inhibition of HCl/ethanol-induced gastric ulcer at 100 mg/kg, ip administered 30 mins prior to HCl/ethanol challenge measured after 1 hr relative to vehicle-treated control
|
Rattus norvegicus
|
74.03
%
|
|
Journal : Med Chem Res
Title : Synthesis and pharmacological evaluation of pyrazolopyrimidopyrimidine derivatives: anti-inflammatory agents with gastroprotective effect in rats.
Year : 2013
First Page : 1
Last Page : 8
Authors : Karoui A, Allouche F, Deghrigue M, Agrebi A, Bouraoui A, Chabchoub F.
Abstract : We report the synthesis of new anti-inflammatory 1,7-dihydropyrazolo[3',4':4,5]pyrimido[1,6-a]pyrimidine 5 from aminocyanopyrazole. All compounds were characterized by physical, chemical and spectral studies. Preliminary pharmacological evaluation of the resulting products showed that compounds 5a, b, f (50-100 mg/kg, i.p) are active anti-inflammatory agents in carrageenan-induced rat paw oedema assay, and their effects are comparable to that of acetylsalicylic-lysine (300 mg/kg, i.p.), used as a reference drug. The nature of substituent (Y, R3) had a pronounced effect on the anti-inflammatory activity. Studies of structure-activity relationships have led to selection of compound ethyl-3,5-dimethyl-7-imino-N (1)-phenyl-1,7-dihydropyrazolo[3',4':4,5]pyrimido[1,6-a]pyrimidine-6-carboxylate, 5f which exhibited the most potent anti-inflammatory activity. In addition, the compounds 5a, b, f showed a significant gastroprotective effect against HCl/EtOH-induced gastric ulcer.
|
Inhibition of sodium fluorescein uptake in OATP1B1-transfected CHO cells at an equimolar substrate-inhibitor concentration of 10 uM
|
Cricetulus griseus
|
120.2
%
|
|
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
|
96.42
%
|
|
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.
|
Displacement of [3H]Cimetidine from histamine H2 receptor (unknown origin)
|
Homo sapiens
|
70.79
nM
|
|
Displacement of [3H]Cimetidine from histamine H2 receptor (unknown origin)
|
Homo sapiens
|
70.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The synthesis and comparative receptor binding affinities of novel, isomeric pyridoindolobenzazepine scaffolds.
Year : 2014
Volume : 24
Issue : 2
First Page : 576
Last Page : 579
Authors : Rajagopalan R, Bandyopadhyaya A, Rajagopalan DR, Rajagopalan P.
Abstract : Compounds 7, 8, and 9, derived from the novel scaffolds 3, 5, and 6, were synthesized and evaluated in vitro. The b,c→c,d shift of the E-phenyl ring resulted in a large decrease (ca. 20- to 1000-fold) in binding to the 5-HT2A, 5-HT2C and H2, receptors, and a modest decrease (ca. 10- to 20-fold) in binding to the 5-HT5A, D2, D5, and α1D, receptors. The b,c→d,e shift resulted in a large decrease in binding to the 5-HT1D, 5-HT2C, 5-HT6, and H1 receptors, a modest decrease in binding to 5-HT1A, 5-HT5A and D2, D5, α2B, and H2 receptors, and a large increase in affinity to the 5-HT3, 5-HT6, and σ1 receptors.
|
Antiulcer activity in albino rat pyloric ligation model assessed as inhibition of gastric volume at 100 mg/kg, po administered as single dose 1 hr prior ligation relative to control
|
Rattus norvegicus
|
14.0
%
|
|
Journal : J. Med. Chem.
Title : Experimental antiulcer drugs. 1. Indole-1-alkanamides and pyrrole-1-alkanamides.
Year : 1977
Volume : 20
Issue : 4
First Page : 537
Last Page : 540
Authors : Bell MR, Zalay AW, Oesterlin R, Clemans SD, Dumas DJ, Bradford JC, Rozitis J.
Abstract : The synthesis and gastric antisecretory activity of a series of indole-1-alkanamides and pyrrole-1-alkanamides are presented. A marked elevation of the pH of the gastric secretions of the rat was observed after oral administration of 100 mg/kg of 2,3-dimethylindole-1-acetamide (2), -1-propionamide (8), and -1-butyramide (13). Replacement of either methyl group by a hydrogen atom or an ethyl radical resulted in greatly diminished activity. In the acetamide and propionamide series the 3-hydroxymethyl-2-methyl (14 and 15) derivatives exhibited activity but only when administered by the subcutaneous route. 2,3-Dimethylindole (18) was active and 2,3,4,5-tetramethylpyrrole-1-acetamide was moderately active. A number of the activ compounds were tested in the mouse mydriasis test for anticholinergic activity and found to be inactive. They were also found to be inactive in blocking histamine-induced acid secretion in the dog.
|
Antiulcer activity in albino rat pyloric ligation model assessed as inhibition of total acid output at 100 mg/kg, po administered as single dose 1 hr prior ligation relative to control
|
Rattus norvegicus
|
37.0
%
|
|
Journal : J. Med. Chem.
Title : Experimental antiulcer drugs. 1. Indole-1-alkanamides and pyrrole-1-alkanamides.
Year : 1977
Volume : 20
Issue : 4
First Page : 537
Last Page : 540
Authors : Bell MR, Zalay AW, Oesterlin R, Clemans SD, Dumas DJ, Bradford JC, Rozitis J.
Abstract : The synthesis and gastric antisecretory activity of a series of indole-1-alkanamides and pyrrole-1-alkanamides are presented. A marked elevation of the pH of the gastric secretions of the rat was observed after oral administration of 100 mg/kg of 2,3-dimethylindole-1-acetamide (2), -1-propionamide (8), and -1-butyramide (13). Replacement of either methyl group by a hydrogen atom or an ethyl radical resulted in greatly diminished activity. In the acetamide and propionamide series the 3-hydroxymethyl-2-methyl (14 and 15) derivatives exhibited activity but only when administered by the subcutaneous route. 2,3-Dimethylindole (18) was active and 2,3,4,5-tetramethylpyrrole-1-acetamide was moderately active. A number of the activ compounds were tested in the mouse mydriasis test for anticholinergic activity and found to be inactive. They were also found to be inactive in blocking histamine-induced acid secretion in the dog.
|
Displacement of [125I]APT from human recombinant histamine H2 receptor expressed in CHO cells after 120 mins by scintillation counting
|
Homo sapiens
|
500.0
nM
|
|
Displacement of [125I]APT from human recombinant histamine H2 receptor expressed in CHO cells after 120 mins by scintillation counting
|
Homo sapiens
|
490.0
nM
|
|
Journal : J Med Chem
Title : Pyrimidine-Based Inhibitors of Dynamin I GTPase Activity: Competitive Inhibition at the Pleckstrin Homology Domain.
Year : 2017
Volume : 60
Issue : 1
First Page : 349
Last Page : 361
Authors : Odell LR, Abdel-Hamid MK, Hill TA, Chau N, Young KA, Deane FM, Sakoff JA, Andersson S, Daniel JA, Robinson PJ, McCluskey A.
Abstract : The large GTPase dynamin mediates membrane fission during clathrin-mediated endocytosis (CME). The aminopyrimidine compounds were reported to disrupt dynamin localization to the plasma membrane via the PH domain and implicate this mechanism in the inhibition of CME. We have used a computational approach of binding site identification, docking, and interaction energy calculations to design and synthesize a new library of aminopyrimidine analogues targeting site-2 of the pleckstrin homology (PH) domain. The optimized analogues showed low micromolar inhibition against both dynamin I (IC50 = 10.6 ± 1.3 to 1.6 ± 0.3 μM) and CME (IC50(CME) = 65.9 ± 7.7 to 3.7 ± 1.1 mM), which makes this series among the more potent inhibitors of dynamin and CME yet reported. In CME and growth inhibition cell-based assays, the data obtained was consistent with dynamin inhibition. CEREP ExpresS profiling identified off-target effects at the cholecystokinin, dopamine D2, histamine H1 and H2, melanocortin, melatonin, muscarinic M1 and M3, neurokinin, opioid KOP and serotonin receptors.
|
Inhibition of human OCT1 expressed in HEK293 cells assessed as decrease in uptake of ASP+ after 2 mins by fluorescence assay
|
Homo sapiens
|
4.13
%
|
|
Journal : J Med Chem
Title : Discovery of Competitive and Noncompetitive Ligands of the Organic Cation Transporter 1 (OCT1; SLC22A1).
Year : 2017
Volume : 60
Issue : 7
First Page : 2685
Last Page : 2696
Authors : Chen EC, Khuri N, Liang X, Stecula A, Chien HC, Yee SW, Huang Y, Sali A, Giacomini KM.
Abstract : Organic cation transporter 1 (OCT1) plays a critical role in the hepatocellular uptake of structurally diverse endogenous compounds and xenobiotics. Here we identified competitive and noncompetitive OCT1-interacting ligands in a library of 1780 prescription drugs by combining in silico and in vitro methods. Ligands were predicted by docking against a comparative model based on a eukaryotic homologue. In parallel, high-throughput screening (HTS) was conducted using the fluorescent probe substrate ASP+ in cells overexpressing human OCT1. Thirty competitive OCT1 ligands, defined as ligands predicted in silico as well as found by HTS, were identified. Of the 167 ligands identified by HTS, five were predicted to potentially cause clinical drug interactions. Finally, virtual screening of 29 332 metabolites predicted 146 competitive OCT1 ligands, of which an endogenous neurotoxin, 1-benzyl-1,2,3,4-tetrahydroisoquinoline, was experimentally validated. In conclusion, by combining docking and in vitro HTS, competitive and noncompetitive ligands of OCT1 can be predicted.
|
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
|
12.6
%
|
|
|
Antibacterial activity against Escherichia coli ATCC 25922 (CO-ADD:GN_001); MIC in CAMBH media using NBS plates, by OD(600)
|
Escherichia coli
|
-4.2
%
|
|
|
Antibacterial activity against Klebsiella pneumoniae MDR ATCC 70063 (CO-ADD:GN_003); MIC in CAMBH media using NBS plates, by OD(600)
|
Klebsiella pneumoniae
|
3.14
%
|
|
|
Antibacterial activity against Pseudomonas aeruginosa ATCC 27853 (CO-ADD:GN_042); MIC in CAMBH media using NBS plates, by OD(600)
|
Pseudomonas aeruginosa
|
12.46
%
|
|
|
Antibacterial activity against Acinetobacter baumannii ATCC 19606 (CO-ADD:GN_034); MIC in CAMBH media using NBS plates, by OD600
|
Acinetobacter baumannii
|
19.7
%
|
|
|
Antifungal activity against Candida albicans ATCC 90028 (CO-ADD:FG_001); MIC in YNB media using NBS plates, by OD630
|
Candida albicans
|
3.16
%
|
|
|
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
|
2.1
%
|
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
-12.58
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
17.13
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.07
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.07
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
