|
Inhibition of beta-lactamase at 100 uM
|
None
|
5.0
%
|
|
Journal : J. Med. Chem.
Title : Identification and prediction of promiscuous aggregating inhibitors among known drugs.
Year : 2003
Volume : 46
Issue : 21
First Page : 4477
Last Page : 4486
Authors : Seidler J, McGovern SL, Doman TN, Shoichet BK.
Abstract : Some small molecules, often hits from screening, form aggregates in solution that inhibit many enzymes. In contrast, drugs are thought to act specifically. To investigate this assumption, 50 unrelated drugs were tested for promiscuous inhibition via aggregation. Each drug was tested against three unrelated model enzymes: beta-lactamase, chymotrypsin, and malate dehydrogenase, none of which are considered targets of these drugs. To be judged promiscuous, the drugs had to inhibit all three enzymes, do so in a time-dependent manner, be sensitive to detergent and to enzyme concentration, and form particles detectable by light scattering. Of the 50 drugs tested, 43 were nonpromiscuous by these criteria. Surprisingly, four of the drugs showed promiscuous, aggregation-based inhibition at concentrations below 100 microM: clotrimazole, benzyl benzoate, nicardipine, and delavirdine. Three other drugs also behaved as aggregation-based inhibitors, but only at high concentrations (about 400 microM). To investigate possible structure-activity relationships among promiscuous drugs, five analogues of the antifungal clotrimazole were studied. Three of these, miconazole, econazole, and sulconazole, were promiscuous but the other two, fluconazole and ketoconazole, were not. Using recursive partitioning, these experimental results were used to develop a model for predicting aggregate-based promiscuity. This model correctly classified 94% of 111 compounds-47 aggregators and 64 nonaggregators-that have been studied for this effect. To evaluate the model, it was used to predict the behavior of 75 drugs not previously investigated for aggregation. Several preliminary points emerge. Most drugs are not promiscuous, even at high concentrations. Nevertheless, at high enough concentrations (20-400 microM), some drugs can aggregate and act promiscuously, suggesting that aggregation may be common among small molecules at micromolar concentrations, at least in biochemical buffers.
|
Inhibition of chymotrypsin at 250 uM
|
unidentified
|
5.0
%
|
|
Journal : J. Med. Chem.
Title : Identification and prediction of promiscuous aggregating inhibitors among known drugs.
Year : 2003
Volume : 46
Issue : 21
First Page : 4477
Last Page : 4486
Authors : Seidler J, McGovern SL, Doman TN, Shoichet BK.
Abstract : Some small molecules, often hits from screening, form aggregates in solution that inhibit many enzymes. In contrast, drugs are thought to act specifically. To investigate this assumption, 50 unrelated drugs were tested for promiscuous inhibition via aggregation. Each drug was tested against three unrelated model enzymes: beta-lactamase, chymotrypsin, and malate dehydrogenase, none of which are considered targets of these drugs. To be judged promiscuous, the drugs had to inhibit all three enzymes, do so in a time-dependent manner, be sensitive to detergent and to enzyme concentration, and form particles detectable by light scattering. Of the 50 drugs tested, 43 were nonpromiscuous by these criteria. Surprisingly, four of the drugs showed promiscuous, aggregation-based inhibition at concentrations below 100 microM: clotrimazole, benzyl benzoate, nicardipine, and delavirdine. Three other drugs also behaved as aggregation-based inhibitors, but only at high concentrations (about 400 microM). To investigate possible structure-activity relationships among promiscuous drugs, five analogues of the antifungal clotrimazole were studied. Three of these, miconazole, econazole, and sulconazole, were promiscuous but the other two, fluconazole and ketoconazole, were not. Using recursive partitioning, these experimental results were used to develop a model for predicting aggregate-based promiscuity. This model correctly classified 94% of 111 compounds-47 aggregators and 64 nonaggregators-that have been studied for this effect. To evaluate the model, it was used to predict the behavior of 75 drugs not previously investigated for aggregation. Several preliminary points emerge. Most drugs are not promiscuous, even at high concentrations. Nevertheless, at high enough concentrations (20-400 microM), some drugs can aggregate and act promiscuously, suggesting that aggregation may be common among small molecules at micromolar concentrations, at least in biochemical buffers.
|
Inhibitory activity when administered intravenously in histamine-stimulated gastric fistula dog at 3 mg/kg, id
|
Canis lupus familiaris
|
97.0
%
|
|
Journal : J. Med. Chem.
Title : Substituted 2-[(2-benzimidazolylsulfinyl)methyl]anilines as potential inhibitors of H+/K+ ATPase.
Year : 1988
Volume : 31
Issue : 6
First Page : 1215
Last Page : 1220
Authors : Adelstein GW, Yen CH, Haack RA, Yu S, Gullikson G, Price DV, Anglin C, Decktor DL, Tsai H, Keith RH.
Abstract : A series of substituted 2-[(2-benzimidazolylsulfinyl)methyl]anilines were synthesized as potential inhibitors of the acid secretory enzyme H+/K+ ATPase. Substitutions on the aniline nitrogen atom resulted in potent enzyme inhibition in vitro but weak activity in gastric fistula dogs. Electron-donating substituents on the aniline ring enhanced in vitro and in vivo potency relative to the unsubstituted analogue. The potency showed a correlation to the calculated pKa of the aniline nitrogen atom. Substitutions on the aniline and benzimidazole rings did not further enhance potency. Di- and trisubstituted aniline derivatives were potent inhibitors of the enzyme system. The preferred combination of substituents were a methoxy group on the benzimidazole ring and a single alkyl group on the aniline ring. One such compound, 76, was an effective inhibitor of acid secretion in the dog and was selected for further pharmacological study.
|
Percent inhibition of histamine-stimulated gastric acid secretion in Heidenhain pouch dog after intraduodenal administration of compound (1 umol/kg)
|
Canis lupus familiaris
|
53.0
%
|
|
Journal : J. Med. Chem.
Title : 2-[[(4-Amino-2-pyridyl)methyl]sulfinyl]benzimidazole H+/K+-ATPase inhibitors. The relationship between pyridine basicity, stability, and activity.
Year : 1989
Volume : 32
Issue : 8
First Page : 1970
Last Page : 1977
Authors : Ife RJ, Dyke CA, Keeling DJ, Meenan E, Meeson ML, Parsons ME, Price CA, Theobald CJ, Underwood AH.
Abstract : The benzimidazole sulfoxide class of antisecretory H+/K+-ATPase inhibitors need to possess high stability under neutral physiological conditions yet rearrange rapidly at low pH to the active sulfenamide 2. Since the initial reaction involves internal nucleophilic attack by the pyridine nitrogen, control of the pyridine pKa is critical. In this paper we show that by utilizing the powerful electron-donating effect of a 4-amino substituent on the pyridine, moderated by the electron-withdrawing effect of a 3- or 5-halogen substituent, a combination of high potency (as inhibitors of histamine-stimulated gastric acid secretion) and good stability under physiological conditions can be obtained. Furthermore, the role of the steric interaction between the 3/5-substituents and the 4-substituent in modifying the electron-donating ability of the 4-amino group is exemplified, and additional factors affecting stability are identified. One compound, in particular, 2-[[(3-chloro-4-morpholino-2- pyridyl)methyl]sulfinyl]-5-methoxy-(1H)-benzimidazole (3a, SK&F 95601), was chosen for further development and evaluation in man.
|
Evaluated for the inhibition of H+/K+ ATPase enzyme from fundic mucosa of white rabbits at 100 uM
|
Oryctolagus cuniculus
|
3.3
uM
|
|
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 vitro evaluation for the inhibition of H+/K+ ATPase at pH < 3 in the gastric glands of isolated rabbit stomach.
|
Oryctolagus cuniculus
|
501.19
nM
|
|
Journal : J. Med. Chem.
Title : (H+,K+)-ATPase inhibiting 2-[(2-pyridylmethyl)sulfinyl]benzimidazoles. 4. A novel series of dimethoxypyridyl-substituted inhibitors with enhanced selectivity. The selection of pantoprazole as a clinical candidate.
Year : 1992
Volume : 35
Issue : 6
First Page : 1049
Last Page : 1057
Authors : Kohl B, Sturm E, Senn-Bilfinger J, Simon WA, Krüger U, Schaefer H, Rainer G, Figala V, Klemm K.
Abstract : [(Pyridylmethyl)sulfinyl]benzimidazoles 1 (PSBs) are a class of highly potent antisecretory (H+,K+)-ATPase inhibitors which need to be activated by acid to form their active principle, the cyclic sulfenamide 4. Selective inhibitors of the (H+,K+)-ATPase in vivo give rise to the nonselective thiophile 4 solely at low pH, thus avoiding interaction with other thiol groups in the body. The propensity to undergo the acid-catalyzed transformation is dependent on the nucleophilic/electrophilic properties of the functional groups involved in the formation of 2 since this step is both rate-determining and pH-dependent. The aim of this study was to identify compounds with high (H+,K+)-ATPase inhibitory activity in stimulated gastric glands possessing acidic pH, but low reactivity (high chemical stability) at neutral pH as reflected by in vitro (Na+,K+)-ATPase inhibitory activity. The critical influence of substituents flanking the pyridine 4-methoxy substituent present in all derivatives was carefully studied. The introduction of a 3-methoxy group gave inhibitors possessing a combination of high potency, similar to omeprazole and lansoprazole, but increased stability. As a result of these studies, compound 1a (INN pantoprazole) was selected as a candidate drug and is currently undergoing phase III clinical studies.
|
Inhibition of H+/K+ ATPase activity in buffered solution (pH 7.4) at concentration 400 mM
|
None
|
95.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Syntheses of 2-[(3,5-dimethyl-4-methoxypyridyl)alkyl]-benzothiazolidine derivatives as a potential gastric H+/K(+)-ATPase inhibitor.
Year : 1998
Volume : 8
Issue : 14
First Page : 1909
Last Page : 1912
Authors : Yoon SH, Seo S, Lee Y, Hwang S, Kim DY.
Abstract : A series of 2-[(3,5-dimethyl-4-methoxypyridyl)alkyl]benzothiazolidine derivatives were synthesized and tested their inhibitory effects on gastric H+/K(+)-ATPase. Compound 4d exhibited potent in vitro inhibitory activity.
|
Compound was evaluated for gastric acid suppression on intravenous administration of a single dose up to 7 hr
|
Equus caballus
|
90.0
%
|
|
Journal : J. Med. Chem.
Title : Perspectives in animal health: old targets and new opportunities.
Year : 2001
Volume : 44
Issue : 5
First Page : 641
Last Page : 659
Authors : Meinke PT.
|
Inhibition of malate dehydrogenase (MDH) at 400 uM
|
None
|
5.0
%
|
|
Journal : J. Med. Chem.
Title : Identification and prediction of promiscuous aggregating inhibitors among known drugs.
Year : 2003
Volume : 46
Issue : 21
First Page : 4477
Last Page : 4486
Authors : Seidler J, McGovern SL, Doman TN, Shoichet BK.
Abstract : Some small molecules, often hits from screening, form aggregates in solution that inhibit many enzymes. In contrast, drugs are thought to act specifically. To investigate this assumption, 50 unrelated drugs were tested for promiscuous inhibition via aggregation. Each drug was tested against three unrelated model enzymes: beta-lactamase, chymotrypsin, and malate dehydrogenase, none of which are considered targets of these drugs. To be judged promiscuous, the drugs had to inhibit all three enzymes, do so in a time-dependent manner, be sensitive to detergent and to enzyme concentration, and form particles detectable by light scattering. Of the 50 drugs tested, 43 were nonpromiscuous by these criteria. Surprisingly, four of the drugs showed promiscuous, aggregation-based inhibition at concentrations below 100 microM: clotrimazole, benzyl benzoate, nicardipine, and delavirdine. Three other drugs also behaved as aggregation-based inhibitors, but only at high concentrations (about 400 microM). To investigate possible structure-activity relationships among promiscuous drugs, five analogues of the antifungal clotrimazole were studied. Three of these, miconazole, econazole, and sulconazole, were promiscuous but the other two, fluconazole and ketoconazole, were not. Using recursive partitioning, these experimental results were used to develop a model for predicting aggregate-based promiscuity. This model correctly classified 94% of 111 compounds-47 aggregators and 64 nonaggregators-that have been studied for this effect. To evaluate the model, it was used to predict the behavior of 75 drugs not previously investigated for aggregation. Several preliminary points emerge. Most drugs are not promiscuous, even at high concentrations. Nevertheless, at high enough concentrations (20-400 microM), some drugs can aggregate and act promiscuously, suggesting that aggregation may be common among small molecules at micromolar concentrations, at least in biochemical buffers.
|
Inhibition of [14C]aminopyrine (AP) accumulation stimulated by dibutyryl cyclic AMP in isolated rabbit parietal cells
|
Oryctolagus cuniculus
|
370.0
nM
|
|
Journal : J. Med. Chem.
Title : Nicotinamide derivatives as a new class of gastric H+/K(+)-ATPase inhibitors. 1. Synthesis and structure-activity relationships of N-substituted 2-(benzhydryl- and benzylsulfinyl)nicotinamides.
Year : 1997
Volume : 40
Issue : 3
First Page : 313
Last Page : 321
Authors : Terauchi H, Tanitame A, Tada K, Nakamura K, Seto Y, Nishikawa Y.
Abstract : A new series of N-Substituted 2-(benzhydryl- and benzylsulfinyl)nicotinamides 7 and 8 were synthesized. Upon acid activation in the acidic environment of the parietal cell, these compounds are converted into their active forms, 2,3-dihydro-3-oxoisothiazolo[5,4-b]pyridines 5, which inhibit gastric H+/K(+)-ATPase. Inhibitory activities against [14C]aminopyrine accumulation stimulated by dibutyryl cAMP in isolated rabbit parietal cells in vitro and histamine-induced gastric acid secretion in pylorus-ligated rats by intraduodenal administration in vivo were evaluated, and the structure-activity relationships were examined. Among the compounds synthesized, 2-[(2,4-dimethoxybenzyl)sulfinyl]-N-(4-pyridyl)nicotinamide (8b) showed potent inhibitory activities in vitro and in vivo equivalent to those of omeprazole, a typical H+/K(+)-ATPase inhibitor. Moreover, 8b was much more stable at neutral and weakly acidic pH than omeprazole, lansoprazole, and pantoprazole. Compound 8b is considered to be a promising agent for treating acid-related gastrointestinal disorders.
|
Antisecretory activity evaluated by the inhibition of 14C -AP uptake in isolated rabbit parietal cells stimulated by dibutyryl cyclic adenosine 3', 5' -monophosphate (dcAMP)
|
Oryctolagus cuniculus
|
280.0
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.
|
Antisecretory activity evaluated by the inhibition of 14C -AP uptake in isolated rabbit parietal cells stimulated by exogenous histamine
|
Oryctolagus cuniculus
|
250.0
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.
|
Percent inhibition of gastric lesions induced by endomethacin was measured, after administration of 10 mg/kg po in rats
|
Rattus norvegicus
|
98.2
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Protective effects of steroid saponins from Paris polyphylla var. yunnanensis on ethanol- or indomethacin-induced gastric mucosal lesions in rats: structural requirement for activity and mode of action.
Year : 2003
Volume : 13
Issue : 6
First Page : 1101
Last Page : 1106
Authors : Matsuda H, Pongpiriyadacha Y, Morikawa T, Kishi A, Kataoka S, Yoshikawa M.
Abstract : The methanolic extract from the rhizomes of Paris polyphylla SM. var. yunnanensis (FR.) H-M. was found to potently inhibit ethanol-induced gastric lesions in rats. Through bioassay-guided separation, four known spirostanol-type steroid saponins, pennogenin 3-O-alpha-L-rhamnopyranosyl(1-->2)-[alpha-L-arabinofuranosyl(1-->4)]-beta-D-glucopyranoside (1), pennogenin 3-O-alpha-L-rhamnopyranosyl(1-->4)-alpha-L-rhamnopyranosyl(1-->4)-[alpha-L-rhamnopyranosyl(1-->2)]-beta-D-glucopyranoside (2), diosgenin 3-O-alpha-L-rhamnopyranosyl(1-->2)-[alpha-L-arabinofuranosyl(1-->4)]-beta-D-glucopyranoside (3), and diosgenin 3-O-alpha-L-rhamnopyranosyl(1-->4)-alpha-L-rhamnopyranosyl(1-->4)-[alpha-L-rhamnopyranosyl(1-->2)]-beta-D-glucopyranoside (4), and a new furostanol-type steroid saponin, parisaponin I (5), together with two known furostanol-type steroid saponins, trigofoenoside A (6) and protogracillin (7), were isolated from the active fraction. Compounds 1-4 (1.25-10 mg/kg, po) strongly inhibited gastric lesions induced by ethanol and indomethacin. With regard to structural requirement of steroid saponins, the 3-O-glycoside moiety and spirostanol structure were found to be essential for the activity and the 17-hydroxyl group in the aglycon part enhanced the protective effects against ethanol-induced gastric lesions. The protective effects of 1 and 3 against ethanol-induced gastric lesions were attenuated by pretreatment with indomethacin and N-ethylmaleimide. Compounds 1 and 3 weakly inhibited acid secretions in pylorus-ligated rats. These findings suggested that endogenous prostaglandins and sulfhydryl compounds were involved in the protective activity.
|
Percent inhibition of gastric lesions induced by endomethacin was measured, after administration of 2.5 mg/kg po in rats
|
Rattus norvegicus
|
42.5
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Protective effects of steroid saponins from Paris polyphylla var. yunnanensis on ethanol- or indomethacin-induced gastric mucosal lesions in rats: structural requirement for activity and mode of action.
Year : 2003
Volume : 13
Issue : 6
First Page : 1101
Last Page : 1106
Authors : Matsuda H, Pongpiriyadacha Y, Morikawa T, Kishi A, Kataoka S, Yoshikawa M.
Abstract : The methanolic extract from the rhizomes of Paris polyphylla SM. var. yunnanensis (FR.) H-M. was found to potently inhibit ethanol-induced gastric lesions in rats. Through bioassay-guided separation, four known spirostanol-type steroid saponins, pennogenin 3-O-alpha-L-rhamnopyranosyl(1-->2)-[alpha-L-arabinofuranosyl(1-->4)]-beta-D-glucopyranoside (1), pennogenin 3-O-alpha-L-rhamnopyranosyl(1-->4)-alpha-L-rhamnopyranosyl(1-->4)-[alpha-L-rhamnopyranosyl(1-->2)]-beta-D-glucopyranoside (2), diosgenin 3-O-alpha-L-rhamnopyranosyl(1-->2)-[alpha-L-arabinofuranosyl(1-->4)]-beta-D-glucopyranoside (3), and diosgenin 3-O-alpha-L-rhamnopyranosyl(1-->4)-alpha-L-rhamnopyranosyl(1-->4)-[alpha-L-rhamnopyranosyl(1-->2)]-beta-D-glucopyranoside (4), and a new furostanol-type steroid saponin, parisaponin I (5), together with two known furostanol-type steroid saponins, trigofoenoside A (6) and protogracillin (7), were isolated from the active fraction. Compounds 1-4 (1.25-10 mg/kg, po) strongly inhibited gastric lesions induced by ethanol and indomethacin. With regard to structural requirement of steroid saponins, the 3-O-glycoside moiety and spirostanol structure were found to be essential for the activity and the 17-hydroxyl group in the aglycon part enhanced the protective effects against ethanol-induced gastric lesions. The protective effects of 1 and 3 against ethanol-induced gastric lesions were attenuated by pretreatment with indomethacin and N-ethylmaleimide. Compounds 1 and 3 weakly inhibited acid secretions in pylorus-ligated rats. These findings suggested that endogenous prostaglandins and sulfhydryl compounds were involved in the protective activity.
|
Percent inhibition of gastric lesions induced by endomethacin was measured, after administration of 5 mg/kg po in rats
|
Rattus norvegicus
|
58.9
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Protective effects of steroid saponins from Paris polyphylla var. yunnanensis on ethanol- or indomethacin-induced gastric mucosal lesions in rats: structural requirement for activity and mode of action.
Year : 2003
Volume : 13
Issue : 6
First Page : 1101
Last Page : 1106
Authors : Matsuda H, Pongpiriyadacha Y, Morikawa T, Kishi A, Kataoka S, Yoshikawa M.
Abstract : The methanolic extract from the rhizomes of Paris polyphylla SM. var. yunnanensis (FR.) H-M. was found to potently inhibit ethanol-induced gastric lesions in rats. Through bioassay-guided separation, four known spirostanol-type steroid saponins, pennogenin 3-O-alpha-L-rhamnopyranosyl(1-->2)-[alpha-L-arabinofuranosyl(1-->4)]-beta-D-glucopyranoside (1), pennogenin 3-O-alpha-L-rhamnopyranosyl(1-->4)-alpha-L-rhamnopyranosyl(1-->4)-[alpha-L-rhamnopyranosyl(1-->2)]-beta-D-glucopyranoside (2), diosgenin 3-O-alpha-L-rhamnopyranosyl(1-->2)-[alpha-L-arabinofuranosyl(1-->4)]-beta-D-glucopyranoside (3), and diosgenin 3-O-alpha-L-rhamnopyranosyl(1-->4)-alpha-L-rhamnopyranosyl(1-->4)-[alpha-L-rhamnopyranosyl(1-->2)]-beta-D-glucopyranoside (4), and a new furostanol-type steroid saponin, parisaponin I (5), together with two known furostanol-type steroid saponins, trigofoenoside A (6) and protogracillin (7), were isolated from the active fraction. Compounds 1-4 (1.25-10 mg/kg, po) strongly inhibited gastric lesions induced by ethanol and indomethacin. With regard to structural requirement of steroid saponins, the 3-O-glycoside moiety and spirostanol structure were found to be essential for the activity and the 17-hydroxyl group in the aglycon part enhanced the protective effects against ethanol-induced gastric lesions. The protective effects of 1 and 3 against ethanol-induced gastric lesions were attenuated by pretreatment with indomethacin and N-ethylmaleimide. Compounds 1 and 3 weakly inhibited acid secretions in pylorus-ligated rats. These findings suggested that endogenous prostaglandins and sulfhydryl compounds were involved in the protective activity.
|
Percent inhibition of gastric lesions induced by endomethacin was measured, after administration of 7.5 mg/kg po in rats
|
Rattus norvegicus
|
86.6
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Protective effects of steroid saponins from Paris polyphylla var. yunnanensis on ethanol- or indomethacin-induced gastric mucosal lesions in rats: structural requirement for activity and mode of action.
Year : 2003
Volume : 13
Issue : 6
First Page : 1101
Last Page : 1106
Authors : Matsuda H, Pongpiriyadacha Y, Morikawa T, Kishi A, Kataoka S, Yoshikawa M.
Abstract : The methanolic extract from the rhizomes of Paris polyphylla SM. var. yunnanensis (FR.) H-M. was found to potently inhibit ethanol-induced gastric lesions in rats. Through bioassay-guided separation, four known spirostanol-type steroid saponins, pennogenin 3-O-alpha-L-rhamnopyranosyl(1-->2)-[alpha-L-arabinofuranosyl(1-->4)]-beta-D-glucopyranoside (1), pennogenin 3-O-alpha-L-rhamnopyranosyl(1-->4)-alpha-L-rhamnopyranosyl(1-->4)-[alpha-L-rhamnopyranosyl(1-->2)]-beta-D-glucopyranoside (2), diosgenin 3-O-alpha-L-rhamnopyranosyl(1-->2)-[alpha-L-arabinofuranosyl(1-->4)]-beta-D-glucopyranoside (3), and diosgenin 3-O-alpha-L-rhamnopyranosyl(1-->4)-alpha-L-rhamnopyranosyl(1-->4)-[alpha-L-rhamnopyranosyl(1-->2)]-beta-D-glucopyranoside (4), and a new furostanol-type steroid saponin, parisaponin I (5), together with two known furostanol-type steroid saponins, trigofoenoside A (6) and protogracillin (7), were isolated from the active fraction. Compounds 1-4 (1.25-10 mg/kg, po) strongly inhibited gastric lesions induced by ethanol and indomethacin. With regard to structural requirement of steroid saponins, the 3-O-glycoside moiety and spirostanol structure were found to be essential for the activity and the 17-hydroxyl group in the aglycon part enhanced the protective effects against ethanol-induced gastric lesions. The protective effects of 1 and 3 against ethanol-induced gastric lesions were attenuated by pretreatment with indomethacin and N-ethylmaleimide. Compounds 1 and 3 weakly inhibited acid secretions in pylorus-ligated rats. These findings suggested that endogenous prostaglandins and sulfhydryl compounds were involved in the protective activity.
|
Percent inhibition of gastric lesions induced by ethanol was measured, after administration of 10 mg/kg po in rats
|
Rattus norvegicus
|
43.1
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Protective effects of steroid saponins from Paris polyphylla var. yunnanensis on ethanol- or indomethacin-induced gastric mucosal lesions in rats: structural requirement for activity and mode of action.
Year : 2003
Volume : 13
Issue : 6
First Page : 1101
Last Page : 1106
Authors : Matsuda H, Pongpiriyadacha Y, Morikawa T, Kishi A, Kataoka S, Yoshikawa M.
Abstract : The methanolic extract from the rhizomes of Paris polyphylla SM. var. yunnanensis (FR.) H-M. was found to potently inhibit ethanol-induced gastric lesions in rats. Through bioassay-guided separation, four known spirostanol-type steroid saponins, pennogenin 3-O-alpha-L-rhamnopyranosyl(1-->2)-[alpha-L-arabinofuranosyl(1-->4)]-beta-D-glucopyranoside (1), pennogenin 3-O-alpha-L-rhamnopyranosyl(1-->4)-alpha-L-rhamnopyranosyl(1-->4)-[alpha-L-rhamnopyranosyl(1-->2)]-beta-D-glucopyranoside (2), diosgenin 3-O-alpha-L-rhamnopyranosyl(1-->2)-[alpha-L-arabinofuranosyl(1-->4)]-beta-D-glucopyranoside (3), and diosgenin 3-O-alpha-L-rhamnopyranosyl(1-->4)-alpha-L-rhamnopyranosyl(1-->4)-[alpha-L-rhamnopyranosyl(1-->2)]-beta-D-glucopyranoside (4), and a new furostanol-type steroid saponin, parisaponin I (5), together with two known furostanol-type steroid saponins, trigofoenoside A (6) and protogracillin (7), were isolated from the active fraction. Compounds 1-4 (1.25-10 mg/kg, po) strongly inhibited gastric lesions induced by ethanol and indomethacin. With regard to structural requirement of steroid saponins, the 3-O-glycoside moiety and spirostanol structure were found to be essential for the activity and the 17-hydroxyl group in the aglycon part enhanced the protective effects against ethanol-induced gastric lesions. The protective effects of 1 and 3 against ethanol-induced gastric lesions were attenuated by pretreatment with indomethacin and N-ethylmaleimide. Compounds 1 and 3 weakly inhibited acid secretions in pylorus-ligated rats. These findings suggested that endogenous prostaglandins and sulfhydryl compounds were involved in the protective activity.
|
Percent inhibition of gastric lesions induced by ethanol was measured, after administration of 15 mg/kg po in rats
|
Rattus norvegicus
|
82.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Protective effects of steroid saponins from Paris polyphylla var. yunnanensis on ethanol- or indomethacin-induced gastric mucosal lesions in rats: structural requirement for activity and mode of action.
Year : 2003
Volume : 13
Issue : 6
First Page : 1101
Last Page : 1106
Authors : Matsuda H, Pongpiriyadacha Y, Morikawa T, Kishi A, Kataoka S, Yoshikawa M.
Abstract : The methanolic extract from the rhizomes of Paris polyphylla SM. var. yunnanensis (FR.) H-M. was found to potently inhibit ethanol-induced gastric lesions in rats. Through bioassay-guided separation, four known spirostanol-type steroid saponins, pennogenin 3-O-alpha-L-rhamnopyranosyl(1-->2)-[alpha-L-arabinofuranosyl(1-->4)]-beta-D-glucopyranoside (1), pennogenin 3-O-alpha-L-rhamnopyranosyl(1-->4)-alpha-L-rhamnopyranosyl(1-->4)-[alpha-L-rhamnopyranosyl(1-->2)]-beta-D-glucopyranoside (2), diosgenin 3-O-alpha-L-rhamnopyranosyl(1-->2)-[alpha-L-arabinofuranosyl(1-->4)]-beta-D-glucopyranoside (3), and diosgenin 3-O-alpha-L-rhamnopyranosyl(1-->4)-alpha-L-rhamnopyranosyl(1-->4)-[alpha-L-rhamnopyranosyl(1-->2)]-beta-D-glucopyranoside (4), and a new furostanol-type steroid saponin, parisaponin I (5), together with two known furostanol-type steroid saponins, trigofoenoside A (6) and protogracillin (7), were isolated from the active fraction. Compounds 1-4 (1.25-10 mg/kg, po) strongly inhibited gastric lesions induced by ethanol and indomethacin. With regard to structural requirement of steroid saponins, the 3-O-glycoside moiety and spirostanol structure were found to be essential for the activity and the 17-hydroxyl group in the aglycon part enhanced the protective effects against ethanol-induced gastric lesions. The protective effects of 1 and 3 against ethanol-induced gastric lesions were attenuated by pretreatment with indomethacin and N-ethylmaleimide. Compounds 1 and 3 weakly inhibited acid secretions in pylorus-ligated rats. These findings suggested that endogenous prostaglandins and sulfhydryl compounds were involved in the protective activity.
|
Percent inhibition of gastric lesions induced by ethanol was measured, after administration of 20 mg/kg po in rats
|
Rattus norvegicus
|
89.4
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Protective effects of steroid saponins from Paris polyphylla var. yunnanensis on ethanol- or indomethacin-induced gastric mucosal lesions in rats: structural requirement for activity and mode of action.
Year : 2003
Volume : 13
Issue : 6
First Page : 1101
Last Page : 1106
Authors : Matsuda H, Pongpiriyadacha Y, Morikawa T, Kishi A, Kataoka S, Yoshikawa M.
Abstract : The methanolic extract from the rhizomes of Paris polyphylla SM. var. yunnanensis (FR.) H-M. was found to potently inhibit ethanol-induced gastric lesions in rats. Through bioassay-guided separation, four known spirostanol-type steroid saponins, pennogenin 3-O-alpha-L-rhamnopyranosyl(1-->2)-[alpha-L-arabinofuranosyl(1-->4)]-beta-D-glucopyranoside (1), pennogenin 3-O-alpha-L-rhamnopyranosyl(1-->4)-alpha-L-rhamnopyranosyl(1-->4)-[alpha-L-rhamnopyranosyl(1-->2)]-beta-D-glucopyranoside (2), diosgenin 3-O-alpha-L-rhamnopyranosyl(1-->2)-[alpha-L-arabinofuranosyl(1-->4)]-beta-D-glucopyranoside (3), and diosgenin 3-O-alpha-L-rhamnopyranosyl(1-->4)-alpha-L-rhamnopyranosyl(1-->4)-[alpha-L-rhamnopyranosyl(1-->2)]-beta-D-glucopyranoside (4), and a new furostanol-type steroid saponin, parisaponin I (5), together with two known furostanol-type steroid saponins, trigofoenoside A (6) and protogracillin (7), were isolated from the active fraction. Compounds 1-4 (1.25-10 mg/kg, po) strongly inhibited gastric lesions induced by ethanol and indomethacin. With regard to structural requirement of steroid saponins, the 3-O-glycoside moiety and spirostanol structure were found to be essential for the activity and the 17-hydroxyl group in the aglycon part enhanced the protective effects against ethanol-induced gastric lesions. The protective effects of 1 and 3 against ethanol-induced gastric lesions were attenuated by pretreatment with indomethacin and N-ethylmaleimide. Compounds 1 and 3 weakly inhibited acid secretions in pylorus-ligated rats. These findings suggested that endogenous prostaglandins and sulfhydryl compounds were involved in the protective activity.
|
Gastric antisecretory activity was tested in rats at 30 mg/kg, po expressed as the percentage of inhibition against the acid output of the control group
|
None
|
100.0
%
|
|
Journal : J. Med. Chem.
Title : 2-[(2-Aminobenzyl)sulfinyl]-1-(2-pyridyl)-1,4,5,6-tetrahydrocyclopent[d]imidazoles as a novel class of gastric H+/K+-ATPase inhibitors.
Year : 1996
Volume : 39
Issue : 2
First Page : 596
Last Page : 604
Authors : Yamada M, Yura T, Morimoto M, Harada T, Yamada K, Honma Y, Kinoshita M, Sugiura M.
Abstract : Substituted 2-sulfinylimidazoles were synthesized and investigated as potential inhibitors of gastric H+/K(+)-ATPase. The 4,5-unsubstituted imidazole series 6-11 and the 1,4,5,6-tetrahydrocyclopent[d]imidazole series 12 were found to be potent inhibitors of the acid secretory enzyme H+/K(+)-ATPase. Structure-activity relationships indicate that the substitution of 2-pyridyl groups at the 1-position of the imidazole moiety combined with (2-aminobenzyl)-sulfinyl groups at the 2-position leads to highly active compounds with a favorable chemical stability. Other substitution patterns in the imidazole moiety result in reducing biological activities. 2-[(2-Aminobenzyl) sulfinyl]-1-[2-(3-methylpyridyl)]-1,4,5,6-tetrahydrocyclopent++ ++ ++ [d]-imidazole (12h, T-776) was selected for further development as a potential clinical candidate. Extensive study on the acid degradation of 12h indicates a mechanism of action different from that of omeprazole, the first H+/K(+)-ATPase inhibitor introduced to the market.
|
Inhibition of gastric proton pump activity of gastric H(+)/K(+) ATPase in Sprague-Dawley rat microsomal vesicles before washing at 10 uM
|
Rattus norvegicus
|
60.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : alpha-Amino acid derivatives as proton pump inhibitors and potent anti-ulcer agents.
Year : 2007
Volume : 42
Issue : 3
First Page : 386
Last Page : 393
Authors : Sharma P, Singh S, Siddiqui TI, Singh VS, Kundu B, Prathipati P, Saxena AK, Dikshit DK, Rastogi L, Dixit C, Gupta MB, Patnaik GK, Dikshit M.
Abstract : In a program to identify new anti-ulcer compounds, a series of N-acyl derivatives of alpha-amino acids were screened for their in vitro H(+)/K(+) ATPase inhibitory activity, and in vivo efficacy in Pylorus ligation model. 3D-QSAR studies were carried out and a representative compound 13 was studied for the nature of its proton pump inhibition.
|
Inhibition of gastric proton pump activity of gastric H(+)/K(+) ATPase in Sprague-Dawley rat microsomal vesicles after washing at 10 uM
|
Rattus norvegicus
|
90.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : alpha-Amino acid derivatives as proton pump inhibitors and potent anti-ulcer agents.
Year : 2007
Volume : 42
Issue : 3
First Page : 386
Last Page : 393
Authors : Sharma P, Singh S, Siddiqui TI, Singh VS, Kundu B, Prathipati P, Saxena AK, Dikshit DK, Rastogi L, Dixit C, Gupta MB, Patnaik GK, Dikshit M.
Abstract : In a program to identify new anti-ulcer compounds, a series of N-acyl derivatives of alpha-amino acids were screened for their in vitro H(+)/K(+) ATPase inhibitory activity, and in vivo efficacy in Pylorus ligation model. 3D-QSAR studies were carried out and a representative compound 13 was studied for the nature of its proton pump inhibition.
|
Inhibition of gastric H+/K(+)-ATPase activity in Sprague-Dawley rat microsomal vesicles at 3 uM in presence of 0.3 mM of ATP
|
Rattus norvegicus
|
38.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : alpha-Amino acid derivatives as proton pump inhibitors and potent anti-ulcer agents.
Year : 2007
Volume : 42
Issue : 3
First Page : 386
Last Page : 393
Authors : Sharma P, Singh S, Siddiqui TI, Singh VS, Kundu B, Prathipati P, Saxena AK, Dikshit DK, Rastogi L, Dixit C, Gupta MB, Patnaik GK, Dikshit M.
Abstract : In a program to identify new anti-ulcer compounds, a series of N-acyl derivatives of alpha-amino acids were screened for their in vitro H(+)/K(+) ATPase inhibitory activity, and in vivo efficacy in Pylorus ligation model. 3D-QSAR studies were carried out and a representative compound 13 was studied for the nature of its proton pump inhibition.
|
Inhibition of gastric H+/K(+)-ATPase activity in Sprague-Dawley rat microsomal vesicles at 10 uM in presence of 0.3 mM of ATP
|
Rattus norvegicus
|
56.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : alpha-Amino acid derivatives as proton pump inhibitors and potent anti-ulcer agents.
Year : 2007
Volume : 42
Issue : 3
First Page : 386
Last Page : 393
Authors : Sharma P, Singh S, Siddiqui TI, Singh VS, Kundu B, Prathipati P, Saxena AK, Dikshit DK, Rastogi L, Dixit C, Gupta MB, Patnaik GK, Dikshit M.
Abstract : In a program to identify new anti-ulcer compounds, a series of N-acyl derivatives of alpha-amino acids were screened for their in vitro H(+)/K(+) ATPase inhibitory activity, and in vivo efficacy in Pylorus ligation model. 3D-QSAR studies were carried out and a representative compound 13 was studied for the nature of its proton pump inhibition.
|
Inhibition of gastric H+/K(+)-ATPase activity in Sprague-Dawley rat microsomal vesicles at 30 uM in presence of 0.3 mM of ATP
|
Rattus norvegicus
|
75.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : alpha-Amino acid derivatives as proton pump inhibitors and potent anti-ulcer agents.
Year : 2007
Volume : 42
Issue : 3
First Page : 386
Last Page : 393
Authors : Sharma P, Singh S, Siddiqui TI, Singh VS, Kundu B, Prathipati P, Saxena AK, Dikshit DK, Rastogi L, Dixit C, Gupta MB, Patnaik GK, Dikshit M.
Abstract : In a program to identify new anti-ulcer compounds, a series of N-acyl derivatives of alpha-amino acids were screened for their in vitro H(+)/K(+) ATPase inhibitory activity, and in vivo efficacy in Pylorus ligation model. 3D-QSAR studies were carried out and a representative compound 13 was studied for the nature of its proton pump inhibition.
|
Inhibition of gastric H+/K(+)-ATPase activity in Sprague-Dawley rat microsomal vesicles at 3 uM in presence of 1.0 mM of ATP
|
Rattus norvegicus
|
38.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : alpha-Amino acid derivatives as proton pump inhibitors and potent anti-ulcer agents.
Year : 2007
Volume : 42
Issue : 3
First Page : 386
Last Page : 393
Authors : Sharma P, Singh S, Siddiqui TI, Singh VS, Kundu B, Prathipati P, Saxena AK, Dikshit DK, Rastogi L, Dixit C, Gupta MB, Patnaik GK, Dikshit M.
Abstract : In a program to identify new anti-ulcer compounds, a series of N-acyl derivatives of alpha-amino acids were screened for their in vitro H(+)/K(+) ATPase inhibitory activity, and in vivo efficacy in Pylorus ligation model. 3D-QSAR studies were carried out and a representative compound 13 was studied for the nature of its proton pump inhibition.
|
Inhibition of gastric H+/K(+)-ATPase activity in Sprague-Dawley rat microsomal vesicles at 10 uM in presence of 1.0 mM of ATP
|
Rattus norvegicus
|
51.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : alpha-Amino acid derivatives as proton pump inhibitors and potent anti-ulcer agents.
Year : 2007
Volume : 42
Issue : 3
First Page : 386
Last Page : 393
Authors : Sharma P, Singh S, Siddiqui TI, Singh VS, Kundu B, Prathipati P, Saxena AK, Dikshit DK, Rastogi L, Dixit C, Gupta MB, Patnaik GK, Dikshit M.
Abstract : In a program to identify new anti-ulcer compounds, a series of N-acyl derivatives of alpha-amino acids were screened for their in vitro H(+)/K(+) ATPase inhibitory activity, and in vivo efficacy in Pylorus ligation model. 3D-QSAR studies were carried out and a representative compound 13 was studied for the nature of its proton pump inhibition.
|
Inhibition of gastric H+/K(+)-ATPase activity in Sprague-Dawley rat microsomal vesicles at 30 uM in presence of 1.0 mM of ATP
|
Rattus norvegicus
|
71.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : alpha-Amino acid derivatives as proton pump inhibitors and potent anti-ulcer agents.
Year : 2007
Volume : 42
Issue : 3
First Page : 386
Last Page : 393
Authors : Sharma P, Singh S, Siddiqui TI, Singh VS, Kundu B, Prathipati P, Saxena AK, Dikshit DK, Rastogi L, Dixit C, Gupta MB, Patnaik GK, Dikshit M.
Abstract : In a program to identify new anti-ulcer compounds, a series of N-acyl derivatives of alpha-amino acids were screened for their in vitro H(+)/K(+) ATPase inhibitory activity, and in vivo efficacy in Pylorus ligation model. 3D-QSAR studies were carried out and a representative compound 13 was studied for the nature of its proton pump inhibition.
|
Inhibition of gastric H+/K(+)-ATPase activity in Sprague-Dawley rat microsomal vesicles at 3 uM in presence of 3.0 mM of ATP
|
Rattus norvegicus
|
34.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : alpha-Amino acid derivatives as proton pump inhibitors and potent anti-ulcer agents.
Year : 2007
Volume : 42
Issue : 3
First Page : 386
Last Page : 393
Authors : Sharma P, Singh S, Siddiqui TI, Singh VS, Kundu B, Prathipati P, Saxena AK, Dikshit DK, Rastogi L, Dixit C, Gupta MB, Patnaik GK, Dikshit M.
Abstract : In a program to identify new anti-ulcer compounds, a series of N-acyl derivatives of alpha-amino acids were screened for their in vitro H(+)/K(+) ATPase inhibitory activity, and in vivo efficacy in Pylorus ligation model. 3D-QSAR studies were carried out and a representative compound 13 was studied for the nature of its proton pump inhibition.
|
Inhibition of gastric H+/K(+)-ATPase activity in Sprague-Dawley rat microsomal vesicles at 10 uM in presence of 3.0 mM of ATP
|
Rattus norvegicus
|
53.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : alpha-Amino acid derivatives as proton pump inhibitors and potent anti-ulcer agents.
Year : 2007
Volume : 42
Issue : 3
First Page : 386
Last Page : 393
Authors : Sharma P, Singh S, Siddiqui TI, Singh VS, Kundu B, Prathipati P, Saxena AK, Dikshit DK, Rastogi L, Dixit C, Gupta MB, Patnaik GK, Dikshit M.
Abstract : In a program to identify new anti-ulcer compounds, a series of N-acyl derivatives of alpha-amino acids were screened for their in vitro H(+)/K(+) ATPase inhibitory activity, and in vivo efficacy in Pylorus ligation model. 3D-QSAR studies were carried out and a representative compound 13 was studied for the nature of its proton pump inhibition.
|
Inhibition of gastric H+/K(+)-ATPase activity in Sprague-Dawley rat microsomal vesicles at 30 uM in presence of 3.0 mM of ATP
|
Rattus norvegicus
|
76.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : alpha-Amino acid derivatives as proton pump inhibitors and potent anti-ulcer agents.
Year : 2007
Volume : 42
Issue : 3
First Page : 386
Last Page : 393
Authors : Sharma P, Singh S, Siddiqui TI, Singh VS, Kundu B, Prathipati P, Saxena AK, Dikshit DK, Rastogi L, Dixit C, Gupta MB, Patnaik GK, Dikshit M.
Abstract : In a program to identify new anti-ulcer compounds, a series of N-acyl derivatives of alpha-amino acids were screened for their in vitro H(+)/K(+) ATPase inhibitory activity, and in vivo efficacy in Pylorus ligation model. 3D-QSAR studies were carried out and a representative compound 13 was studied for the nature of its proton pump inhibition.
|
Inhibition of p-NPPase in Sprague-Dawley rat microsomal vesicles at 3 uM in presence of 1.0 mM of p-NPP
|
Rattus norvegicus
|
28.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : alpha-Amino acid derivatives as proton pump inhibitors and potent anti-ulcer agents.
Year : 2007
Volume : 42
Issue : 3
First Page : 386
Last Page : 393
Authors : Sharma P, Singh S, Siddiqui TI, Singh VS, Kundu B, Prathipati P, Saxena AK, Dikshit DK, Rastogi L, Dixit C, Gupta MB, Patnaik GK, Dikshit M.
Abstract : In a program to identify new anti-ulcer compounds, a series of N-acyl derivatives of alpha-amino acids were screened for their in vitro H(+)/K(+) ATPase inhibitory activity, and in vivo efficacy in Pylorus ligation model. 3D-QSAR studies were carried out and a representative compound 13 was studied for the nature of its proton pump inhibition.
|
Inhibition of p-NPPase in Sprague-Dawley rat microsomal vesicles at 10 uM in presence of 1.0 mM of p-NPP
|
Rattus norvegicus
|
54.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : alpha-Amino acid derivatives as proton pump inhibitors and potent anti-ulcer agents.
Year : 2007
Volume : 42
Issue : 3
First Page : 386
Last Page : 393
Authors : Sharma P, Singh S, Siddiqui TI, Singh VS, Kundu B, Prathipati P, Saxena AK, Dikshit DK, Rastogi L, Dixit C, Gupta MB, Patnaik GK, Dikshit M.
Abstract : In a program to identify new anti-ulcer compounds, a series of N-acyl derivatives of alpha-amino acids were screened for their in vitro H(+)/K(+) ATPase inhibitory activity, and in vivo efficacy in Pylorus ligation model. 3D-QSAR studies were carried out and a representative compound 13 was studied for the nature of its proton pump inhibition.
|
Inhibition of p-NPPase in Sprague-Dawley rat microsomal vesicles at 30 uM in presence of 1.0 mM of p-NPP
|
Rattus norvegicus
|
77.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : alpha-Amino acid derivatives as proton pump inhibitors and potent anti-ulcer agents.
Year : 2007
Volume : 42
Issue : 3
First Page : 386
Last Page : 393
Authors : Sharma P, Singh S, Siddiqui TI, Singh VS, Kundu B, Prathipati P, Saxena AK, Dikshit DK, Rastogi L, Dixit C, Gupta MB, Patnaik GK, Dikshit M.
Abstract : In a program to identify new anti-ulcer compounds, a series of N-acyl derivatives of alpha-amino acids were screened for their in vitro H(+)/K(+) ATPase inhibitory activity, and in vivo efficacy in Pylorus ligation model. 3D-QSAR studies were carried out and a representative compound 13 was studied for the nature of its proton pump inhibition.
|
Inhibition of p-NPPase in Sprague-Dawley rat microsomal vesicles at 3 uM in presence of 3.0 mM of p-NPP
|
Rattus norvegicus
|
28.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : alpha-Amino acid derivatives as proton pump inhibitors and potent anti-ulcer agents.
Year : 2007
Volume : 42
Issue : 3
First Page : 386
Last Page : 393
Authors : Sharma P, Singh S, Siddiqui TI, Singh VS, Kundu B, Prathipati P, Saxena AK, Dikshit DK, Rastogi L, Dixit C, Gupta MB, Patnaik GK, Dikshit M.
Abstract : In a program to identify new anti-ulcer compounds, a series of N-acyl derivatives of alpha-amino acids were screened for their in vitro H(+)/K(+) ATPase inhibitory activity, and in vivo efficacy in Pylorus ligation model. 3D-QSAR studies were carried out and a representative compound 13 was studied for the nature of its proton pump inhibition.
|
Inhibition of p-NPPase in Sprague-Dawley rat microsomal vesicles at 10 uM in presence of 3.0 mM of p-NPP
|
Rattus norvegicus
|
52.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : alpha-Amino acid derivatives as proton pump inhibitors and potent anti-ulcer agents.
Year : 2007
Volume : 42
Issue : 3
First Page : 386
Last Page : 393
Authors : Sharma P, Singh S, Siddiqui TI, Singh VS, Kundu B, Prathipati P, Saxena AK, Dikshit DK, Rastogi L, Dixit C, Gupta MB, Patnaik GK, Dikshit M.
Abstract : In a program to identify new anti-ulcer compounds, a series of N-acyl derivatives of alpha-amino acids were screened for their in vitro H(+)/K(+) ATPase inhibitory activity, and in vivo efficacy in Pylorus ligation model. 3D-QSAR studies were carried out and a representative compound 13 was studied for the nature of its proton pump inhibition.
|
Inhibition of p-NPPase in Sprague-Dawley rat microsomal vesicles at 30 uM in presence of 3.0 mM of p-NPP
|
Rattus norvegicus
|
78.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : alpha-Amino acid derivatives as proton pump inhibitors and potent anti-ulcer agents.
Year : 2007
Volume : 42
Issue : 3
First Page : 386
Last Page : 393
Authors : Sharma P, Singh S, Siddiqui TI, Singh VS, Kundu B, Prathipati P, Saxena AK, Dikshit DK, Rastogi L, Dixit C, Gupta MB, Patnaik GK, Dikshit M.
Abstract : In a program to identify new anti-ulcer compounds, a series of N-acyl derivatives of alpha-amino acids were screened for their in vitro H(+)/K(+) ATPase inhibitory activity, and in vivo efficacy in Pylorus ligation model. 3D-QSAR studies were carried out and a representative compound 13 was studied for the nature of its proton pump inhibition.
|
Inhibition of p-NPPase in Sprague-Dawley rat microsomal vesicles at 10 uM in presence of 5.0 mM of p-NPP
|
Rattus norvegicus
|
48.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : alpha-Amino acid derivatives as proton pump inhibitors and potent anti-ulcer agents.
Year : 2007
Volume : 42
Issue : 3
First Page : 386
Last Page : 393
Authors : Sharma P, Singh S, Siddiqui TI, Singh VS, Kundu B, Prathipati P, Saxena AK, Dikshit DK, Rastogi L, Dixit C, Gupta MB, Patnaik GK, Dikshit M.
Abstract : In a program to identify new anti-ulcer compounds, a series of N-acyl derivatives of alpha-amino acids were screened for their in vitro H(+)/K(+) ATPase inhibitory activity, and in vivo efficacy in Pylorus ligation model. 3D-QSAR studies were carried out and a representative compound 13 was studied for the nature of its proton pump inhibition.
|
Inhibition of p-NPPase in Sprague-Dawley rat microsomal vesicles at 30 uM in presence of 5.0 mM of p-NPP
|
Rattus norvegicus
|
79.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : alpha-Amino acid derivatives as proton pump inhibitors and potent anti-ulcer agents.
Year : 2007
Volume : 42
Issue : 3
First Page : 386
Last Page : 393
Authors : Sharma P, Singh S, Siddiqui TI, Singh VS, Kundu B, Prathipati P, Saxena AK, Dikshit DK, Rastogi L, Dixit C, Gupta MB, Patnaik GK, Dikshit M.
Abstract : In a program to identify new anti-ulcer compounds, a series of N-acyl derivatives of alpha-amino acids were screened for their in vitro H(+)/K(+) ATPase inhibitory activity, and in vivo efficacy in Pylorus ligation model. 3D-QSAR studies were carried out and a representative compound 13 was studied for the nature of its proton pump inhibition.
|
Inhibition of p-NPPase in Sprague-Dawley rat microsomal vesicles at 100 uM in presence of 5.0 mM of p-NPP
|
Rattus norvegicus
|
96.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : alpha-Amino acid derivatives as proton pump inhibitors and potent anti-ulcer agents.
Year : 2007
Volume : 42
Issue : 3
First Page : 386
Last Page : 393
Authors : Sharma P, Singh S, Siddiqui TI, Singh VS, Kundu B, Prathipati P, Saxena AK, Dikshit DK, Rastogi L, Dixit C, Gupta MB, Patnaik GK, Dikshit M.
Abstract : In a program to identify new anti-ulcer compounds, a series of N-acyl derivatives of alpha-amino acids were screened for their in vitro H(+)/K(+) ATPase inhibitory activity, and in vivo efficacy in Pylorus ligation model. 3D-QSAR studies were carried out and a representative compound 13 was studied for the nature of its proton pump inhibition.
|
Gastroprotective effect in ddY rat assessed as inhibition of ethanol-induced gastric mucosal lesions at 10 mg/kg, po administered 1 hr prior to ethanol challenge relative to control
|
Rattus norvegicus
|
43.1
%
|
|
Journal : J. Nat. Prod.
Title : Triterpene saponins with gastroprotective effects from tea seed (the seeds of Camellia sinensis).
Year : 2006
Volume : 69
Issue : 2
First Page : 185
Last Page : 190
Authors : Morikawa T, Li N, Nagatomo A, Matsuda H, Li X, Yoshikawa M.
Abstract : Six new triterpene saponins, theasaponins A(1) (1), A(2) (2), A(3) (3), F(1) (4), F(2) (5), and F(3) (6), were isolated from the saponin fraction of the seeds of Camellia sinensis. The stereostructures of 1-6 were elucidated on the basis of chemical and physicochemical evidence. Theasaponin A(2) (2) showed an inhibitory effect on ethanol-induced gastric mucosal lesions in rats at a dose of 5.0 mg/kg, p.o., and its activity was more potent than that of omeplazole. Structure-activity relationships for theasaponins on ethanol-induced gastroprotective activities may be suggested as follows: (1) the 28-acetyl moiety enhances activity; (2) theasaponins having a 23-aldehyde group exhibit more potent activities than those with a 23-hydroxymethyl group or a 23-methoxycarbonyl group.
|
Gastroprotective effect in ddY rat assessed as inhibition of ethanol-induced gastric mucosal lesions at 15 mg/kg, po administered 1 hr prior to ethanol challenge relative to control
|
Rattus norvegicus
|
82.0
%
|
|
Journal : J. Nat. Prod.
Title : Triterpene saponins with gastroprotective effects from tea seed (the seeds of Camellia sinensis).
Year : 2006
Volume : 69
Issue : 2
First Page : 185
Last Page : 190
Authors : Morikawa T, Li N, Nagatomo A, Matsuda H, Li X, Yoshikawa M.
Abstract : Six new triterpene saponins, theasaponins A(1) (1), A(2) (2), A(3) (3), F(1) (4), F(2) (5), and F(3) (6), were isolated from the saponin fraction of the seeds of Camellia sinensis. The stereostructures of 1-6 were elucidated on the basis of chemical and physicochemical evidence. Theasaponin A(2) (2) showed an inhibitory effect on ethanol-induced gastric mucosal lesions in rats at a dose of 5.0 mg/kg, p.o., and its activity was more potent than that of omeplazole. Structure-activity relationships for theasaponins on ethanol-induced gastroprotective activities may be suggested as follows: (1) the 28-acetyl moiety enhances activity; (2) theasaponins having a 23-aldehyde group exhibit more potent activities than those with a 23-hydroxymethyl group or a 23-methoxycarbonyl group.
|
Gastroprotective effect in ddY rat assessed as inhibition of ethanol-induced gastric mucosal lesions at 20 mg/kg, po administered 1 hr prior to ethanol challenge relative to control
|
Rattus norvegicus
|
89.4
%
|
|
Journal : J. Nat. Prod.
Title : Triterpene saponins with gastroprotective effects from tea seed (the seeds of Camellia sinensis).
Year : 2006
Volume : 69
Issue : 2
First Page : 185
Last Page : 190
Authors : Morikawa T, Li N, Nagatomo A, Matsuda H, Li X, Yoshikawa M.
Abstract : Six new triterpene saponins, theasaponins A(1) (1), A(2) (2), A(3) (3), F(1) (4), F(2) (5), and F(3) (6), were isolated from the saponin fraction of the seeds of Camellia sinensis. The stereostructures of 1-6 were elucidated on the basis of chemical and physicochemical evidence. Theasaponin A(2) (2) showed an inhibitory effect on ethanol-induced gastric mucosal lesions in rats at a dose of 5.0 mg/kg, p.o., and its activity was more potent than that of omeplazole. Structure-activity relationships for theasaponins on ethanol-induced gastroprotective activities may be suggested as follows: (1) the 28-acetyl moiety enhances activity; (2) theasaponins having a 23-aldehyde group exhibit more potent activities than those with a 23-hydroxymethyl group or a 23-methoxycarbonyl group.
|
Inhibition of H+/K+ATPase in pig gastric microsome assessed as liberation of inorganic phosphate using ATP at 10 uM relative to control
|
Sus scrofa
|
39.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : A reverse method for diversity introduction of benzimidazole to synthesize H(+)/K(+)-ATP enzyme inhibitors.
Year : 2011
Volume : 21
Issue : 14
First Page : 4189
Last Page : 4192
Authors : Yan Y, Liu Z, Zhang J, Xu R, Hu X, Liu G.
Abstract : A series of 2-[(2-pyridylmethyl)sulfinyl]benzimidazole derivatives were synthesized via a solution phase synthetic route using a reversal method of diversity introduction. Using this synthetic strategy, we obtained two key intermediates (4-A and 4-B) simultaneously, which allows us to introduce diversity points onto the benzimidazole part of the final product under reliable reaction conditions to identify potent H(+)/K(+)-ATP enzyme inhibitors. Compound 14l (IC(50)=1.6×10(-5)M) was comparable with H(+)/K(+)-ATP enzyme inhibitor in vitro.
|
Antiulcerogenic activity in Kunming mouse assessed as inhibition of ethanol-induced gastric ulcer at 13.4 mg/kg, po qd for 5 days measured 1 hr post last dose relative to control
|
Mus musculus
|
36.74
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and antigastric ulcer activity of novel 5-isoproyl-3,8-dimethylazulene derivatives.
Year : 2011
Volume : 21
Issue : 19
First Page : 5722
Last Page : 5725
Authors : Zhang LY, Yang F, Shi WQ, Zhang P, Li Y, Yin SF.
Abstract : 5-Isoproyl-3,8-dimethylazulene derivatives were synthesized and evaluated for antigastric ulcer activity in vivo. Some of them possess the best activity against gastric ulcer with ulcer index values lower than the drug reference (omeprazole). The structure-activity relationship (SAR) shows that the lipophilic flat structure contributes to quite potent antigastric ulcer activity.
|
Antiprotozoan activity against Trichomonas vaginalis GT3 trophozoites compound treated for 48 hrs measured after 48 hrs washout period
|
Trichomonas vaginalis
|
121.6
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Antiprotozoal activity of proton-pump inhibitors.
Year : 2011
Volume : 21
Issue : 24
First Page : 7351
Last Page : 7354
Authors : Pérez-Villanueva J, Romo-Mancillas A, Hernández-Campos A, Yépez-Mulia L, Hernández-Luis F, Castillo R.
Abstract : Parasitic diseases are still a major health problem in developing countries. In our effort to find new antiparasitic agents, in this Letter we report the in vitro antiprotozoal activity of omeprazole, lansoprazole, rabeprazole and pantoprazole against Trichomonas vaginalis, Giardia intestinalis and Entamoeba histolytica. Molecular modeling studies were an important tool to highlight the potential antiprotozoal activity of these drugs. Experimental evaluations revealed a strong activity for all compounds tested. Rabeprazole and pantoprazole were the most active compounds, having IC(50) values in the nanomolar range, which were even better than metronidazole, the drug of choice for these parasites.
|
Antiprotozoan activity against Giardia intestinalis IMSS:0989:1 trophozoites compound treated for 48 hrs measured after 48 hrs washout period
|
Giardia intestinalis
|
95.5
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Antiprotozoal activity of proton-pump inhibitors.
Year : 2011
Volume : 21
Issue : 24
First Page : 7351
Last Page : 7354
Authors : Pérez-Villanueva J, Romo-Mancillas A, Hernández-Campos A, Yépez-Mulia L, Hernández-Luis F, Castillo R.
Abstract : Parasitic diseases are still a major health problem in developing countries. In our effort to find new antiparasitic agents, in this Letter we report the in vitro antiprotozoal activity of omeprazole, lansoprazole, rabeprazole and pantoprazole against Trichomonas vaginalis, Giardia intestinalis and Entamoeba histolytica. Molecular modeling studies were an important tool to highlight the potential antiprotozoal activity of these drugs. Experimental evaluations revealed a strong activity for all compounds tested. Rabeprazole and pantoprazole were the most active compounds, having IC(50) values in the nanomolar range, which were even better than metronidazole, the drug of choice for these parasites.
|
Antiprotozoan activity against Entamoeba histolytica HM1-IMSS trophozoites compound treated for 48 hrs measured after 48 hrs washout period
|
Entamoeba histolytica
|
492.2
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Antiprotozoal activity of proton-pump inhibitors.
Year : 2011
Volume : 21
Issue : 24
First Page : 7351
Last Page : 7354
Authors : Pérez-Villanueva J, Romo-Mancillas A, Hernández-Campos A, Yépez-Mulia L, Hernández-Luis F, Castillo R.
Abstract : Parasitic diseases are still a major health problem in developing countries. In our effort to find new antiparasitic agents, in this Letter we report the in vitro antiprotozoal activity of omeprazole, lansoprazole, rabeprazole and pantoprazole against Trichomonas vaginalis, Giardia intestinalis and Entamoeba histolytica. Molecular modeling studies were an important tool to highlight the potential antiprotozoal activity of these drugs. Experimental evaluations revealed a strong activity for all compounds tested. Rabeprazole and pantoprazole were the most active compounds, having IC(50) values in the nanomolar range, which were even better than metronidazole, the drug of choice for these parasites.
|
HARVARD: Inhibition of liver stage Plasmodium berghei infection in HepG2 cells
|
Plasmodium berghei
|
680.0
nM
|
|
Journal : Proc. Natl. Acad. Sci. U.S.A.
Title : Liver-stage malaria parasites vulnerable to diverse chemical scaffolds.
Year : 2012
Volume : 109
Issue : 22
First Page : 8511
Last Page : 8516
Authors : Derbyshire ER, Prudêncio M, Mota MM, Clardy J.
Abstract : Human malaria infection begins with a one-time asymptomatic liver stage followed by a cyclic symptomatic blood stage. All high-throughput malaria drug discovery efforts have focused on the cyclic blood stage, which has limited potential for the prophylaxis, transmission blocking, and eradication efforts that will be needed in the future. To address these unmet needs, a high-throughput phenotypic liver-stage Plasmodium parasite screen was developed to systematically identify molecules with liver-stage efficacy. The screen recapitulates liver-stage infection by isolating luciferase-expressing Plasmodium berghei parasites directly from the salivary glands of infected mosquitoes, adding them to confluent human liver cells in 384-well plates, and measuring luciferase activity after a suitable incubation period. Screening 5,375 known bioactive compounds identified 37 liver-stage malaria inhibitors with diverse modes of action, as shown by inhibition time course experiments. Further analysis of the hits in the Food and Drug Administration-approved drug subset revealed compounds that seem to act specifically on the liver stage of infection, suggesting that this phase of the parasite's life cycle presents a promising area for new drug discovery. Notably, many active compounds in this screen have molecular structures and putative targets distinctly different from those of known antimalarial agents.
|
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
|
15.9
%
|
|
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
|
29.5
%
|
|
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
|
11.3
%
|
|
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.
|
Antiulcerogenic activity in ethanol-induced gastric ulcer Swiss albino mouse model assessed as inhibition of ulceration at 3.6 mg/kg administered intragastrically for 3 days relative to control
|
Mus musculus
|
68.3
%
|
|
Journal : Bioorg. Med. Chem.
Title : Design, synthesis and pharmacological evaluation of omeprazole-like agents with anti-inflammatory activity.
Year : 2013
Volume : 21
Issue : 7
First Page : 1661
Last Page : 1670
Authors : El-Nezhawy AO, Biuomy AR, Hassan FS, Ismaiel AK, Omar HA.
Abstract : A new series of novel benzimidazole derivatives containing substituted pyrid-2-yl moiety and polyhydroxy sugar conjugated to the N-benzimidazole moiety has been synthesized and evaluated as orally bioavailable anti-inflammatory agents with anti-ulcerogenic activity. The anti-inflammatory and anti-ulcerogenic activities of these compounds were compared to diclofenac and omeprazole, respectively. In carrageenan-induced paw oedema assay, 2-methyl-N-((3,4-dimethoxypyridin-2-yl)methyl)-1H-benzimidazol-5-amine (12d) and 1-(1,2,3,5-tetrahydroxy-α-D-mannofuranose)-5-(((3,4-dimethoxypyridin-2yl)methyl)amino)-2-methyl-1H-benzimidazole (15d) displayed dose-dependent anti-inflammatory activities by decreasing the inflammation by 62% and 72%, respectively which is comparable to that of diclofenac (73%). In contrast to diclofenac, the anti-inflammatory activity of these compounds was not only free from any side effects on the gastric mucosa but also showed significant anti-ulcerogenic activity in rat pyloric ligation and ethanol-induced gastric ulcer models similar to that of omeprazole. Together, these findings suggest that 12d and 15d are potent anti-inflammatory agents with concurrent anti-ulcerogenic activity and support its clinical promise as a component of therapeutic strategies for inflammation, for which the gastric side effects are always a major limitation.
|
Inhibition of CYP2C19 (unknown origin) at 24 uM by luminescent readout-based method
|
Homo sapiens
|
93.4
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Phenoxymethyl 1,3-oxazoles and 1,2,4-oxadiazoles as potent and selective agonists of free fatty acid receptor 1 (GPR40).
Year : 2015
Volume : 25
Issue : 16
First Page : 3105
Last Page : 3111
Authors : Zahanich I, Kondratov I, Naumchyk V, Kheylik Y, Platonov M, Zozulya S, Krasavin M.
Abstract : A screening hit that showed a weak (EC50 = 18 μM), partial agonistic effect on GPR40 was used a prototype for expedited hit expansion effort using a set of advanced building blocks. The latter yielded several 1,3-oxazoles and 1,2,4-oxadiazoles with significantly improved potency (best EC50 = 0.058 μM). The lead compounds in each chemotype showed a very good ADME profile (aqueous solubility, plasma protein binding, microsomal stability and membrane permeability) and no appreciable inhibition of key cytochromes P450. The compounds reported are significant new starting points for further preclinical development of future diabetic agents with a mechanism of action for which a first-in-class agent is yet to be approved.
|
Inhibition of CYP2C19 (unknown origin) at 24 uM by P450-glo assay
|
Homo sapiens
|
93.4
%
|
|
Journal : Bioorg. Med. Chem.
Title : Novel free fatty acid receptor 1 (GPR40) agonists based on 1,3,4-thiadiazole-2-carboxamide scaffold.
Year : 2016
Volume : 24
Issue : 13
First Page : 2954
Last Page : 2963
Authors : Krasavin M, Lukin A, Zhurilo N, Kovalenko A, Zahanich I, Zozulya S, Moore D, Tikhonova IG.
Abstract : Free fatty acid receptor 1 (FFA1), previously known as GPR40 is a G protein-coupled receptor and a new target for treatment of type 2 diabetes. Two series of FFA1 agonists utilizing a 1,3,4-thiadiazole-2-caboxamide scaffold were synthetized. Both series offered significant improvement of the potency compared to the previously described 1,3,4-thiadiazole-based FFA1 agonists and high selectivity for FFA1. Molecular docking predicts new aromatic interactions with the receptor that improve agonist potency. The most potent compounds from both series were profiled for in vitro ADME properties (plasma and metabolic stability, LogD, plasma protein binding, hERG binding and CYP inhibition). One series suffered very rapid degradation in plasma and in presence of mouse liver microsomes. However, the other series delivered a lead compound that displayed a reasonable ADME profile together with the improved FFA1 potency.
|
Anti-Trichomonas activity against Trichomonas vaginalis JT assessed as reduction in parasite growth after 24 hrs by haemocytometry
|
Trichomonas vaginalis
|
121.6
nM
|
|
Journal : Eur J Med Chem
Title : Recent developments in anti-Trichomonas research: An update review.
Year : 2018
Volume : 143
First Page : 232
Last Page : 243
Authors : Bala V, Chhonker YS.
Abstract : Trichomonas vaginalis is a major non-viral sexually-transmitted infection resulted into serious obstetrical and gynecological troubles. The increasing resistance to nitroimidazole therapy and recurrence makes it crucial to develop new drugs against trichomoniasis. Over the past few years, a large number of research articles highlighting the synthetic and natural product research to combat Trichomonas vaginalis have been published. Electronic databases were searched to collect all data from the year 2006 through June 2017 for anti-Trichomonas activity potential of synthetic and natural products. This review article put together the synthetic and natural product research to find out an effective metronidazole alternative to cure trichomoniasis.
|
Inhibition of hydrogen potassium ATPase in goat stomach mucosal membrane assessed as decrease in inorganic phosphate production using ATP as substrate after 10 to 15 mins by spectrophotometric analysis
|
Capra hircus
|
980.0
nM
|
|
Journal : Eur J Med Chem
Title : Substituted methoxybenzyl-sulfonyl-1H-benzo[d]imidazoles evaluated as effective H+/K+-ATPase inhibitors and anti-ulcer therapeutics.
Year : 2017
Volume : 139
First Page : 454
Last Page : 460
Authors : Rajesh R, Manikandan A, Sivakumar A, Ramasubbu C, Nagaraju N.
Abstract : Efforts were made to synthesize a series of substituted methoxybenzyl-sulfonyl-1H-benzo[d]imidazole derivatives (8a-l) and investigate their anti-ulcer therapeutics. Prior to evaluating antiulcer potentials of 8a-l, a preliminary binding assay against H+/K+-ATPase from goat gastric mucosa was carried out, since it plays an important role in the ulcer development. In order to get more insight into the binding mode of the compounds to H+/K+-ATPase, a molecular docking study was carried out and the best binding affinities were unveiled. Many of the substituted methoxybenzyl-sulfonyl-1H-benzo[d]imidazole derivatives (8a-l) were active for the proposed activity. The key finding was that, least inhibitory constant (ki) values of 8a-l were found between 0.02 and 1.8 μM in the molecular docking study. Almost the same range was reflected/correlated in the H+/K+-ATPase inhibition assay (IC50 0.14-1.29 μM). Remarkably, compounds 8a-l showed a relative activity percentage range of 72-92%. Efficient HRBC membrane stabilization activity of 8a-l ensured the non-harm/safety and the suitability/alternative towards anti-ulcer therapy.
|
Inhibition of hydrogen potassium ATPase in goat stomach mucosal membrane assessed as decrease in inorganic phosphate production using ATP as substrate after 10 to 15 mins by spectrophotometric analysis relative to omeprazole
|
Capra hircus
|
82.12
%
|
|
Journal : Eur J Med Chem
Title : Substituted methoxybenzyl-sulfonyl-1H-benzo[d]imidazoles evaluated as effective H+/K+-ATPase inhibitors and anti-ulcer therapeutics.
Year : 2017
Volume : 139
First Page : 454
Last Page : 460
Authors : Rajesh R, Manikandan A, Sivakumar A, Ramasubbu C, Nagaraju N.
Abstract : Efforts were made to synthesize a series of substituted methoxybenzyl-sulfonyl-1H-benzo[d]imidazole derivatives (8a-l) and investigate their anti-ulcer therapeutics. Prior to evaluating antiulcer potentials of 8a-l, a preliminary binding assay against H+/K+-ATPase from goat gastric mucosa was carried out, since it plays an important role in the ulcer development. In order to get more insight into the binding mode of the compounds to H+/K+-ATPase, a molecular docking study was carried out and the best binding affinities were unveiled. Many of the substituted methoxybenzyl-sulfonyl-1H-benzo[d]imidazole derivatives (8a-l) were active for the proposed activity. The key finding was that, least inhibitory constant (ki) values of 8a-l were found between 0.02 and 1.8 μM in the molecular docking study. Almost the same range was reflected/correlated in the H+/K+-ATPase inhibition assay (IC50 0.14-1.29 μM). Remarkably, compounds 8a-l showed a relative activity percentage range of 72-92%. Efficient HRBC membrane stabilization activity of 8a-l ensured the non-harm/safety and the suitability/alternative towards anti-ulcer therapy.
|
Inhibition of H+/K+-ATPase in sheep stomach parietal cells assessed as reduction in inorganic phosphate liberation using ATP as substrate measured after 10 to 15 mins
|
Ovis aries
|
46.14
ug.mL-1
|
|
Journal : MedChemComm
Title : Synthesis of benzo[<i>d</i>]thiazole-hydrazone analogues: molecular docking and SAR studies of potential H<sup>+</sup>/K<sup>+</sup> ATPase inhibitors and anti-inflammatory agents.
Year : 2017
Volume : 8
Issue : 6
First Page : 1173
Last Page : 1189
Authors : Wang SM, Zha GF, Rakesh KP, Darshini N, Shubhavathi T, Vivek HK, Mallesha N, Qin HL.
Abstract : A series of new benzo[<i>d</i>]thiazole-hydrazones were synthesized and characterized by analytical and spectroscopic techniques. All the compounds were screened for their <i>in vitro</i> inhibition of H<sup>+</sup>/K<sup>+</sup> ATPase and anti-inflammatory effects. The results revealed that compounds <b>6-8</b>, <b>13-15</b>, <b>18-20</b>, <b>22</b>, <b>23</b> and <b>27-30</b> displayed excellent inhibitory activity against H<sup>+</sup>/K<sup>+</sup> ATPase, and their IC<sub>50</sub> values were lower than those of the standard compound omeprazole. Compounds <b>2-5</b>, <b>9-12</b>, <b>28</b> and <b>30</b> exhibited better anti-inflammatory activity in comparison to the standard compound indomethacin. Studies of the structure-activity relationship (SAR) showed that electron-donating groups (OH and OCH<sub>3</sub>) favored inhibitory activity against H<sup>+</sup>/K<sup>+</sup> ATPase, whereas electron-withdrawing groups (F, Cl, Br and NO<sub>2</sub>) favored anti-inflammatory activity, and derivatives with both electron-donating (OH and OCH<sub>3</sub>) and electron-withdrawing (Br) groups (<b>16-18</b>) displayed reasonable activity, whereas aliphatic analogues (<b>24-26</b>) exhibited less activity and heterocyclic analogues (<b>27-30</b>) displayed moderate activity in both biological studies. Molecular docking studies were performed for all the synthesized compounds, among which compounds <b>19</b> and <b>20</b> exhibited the highest docking scores for inhibitory activity against H<sup>+</sup>/K<sup>+</sup> ATPase, whereas compounds <b>10</b> and <b>12</b> displayed the highest docking scores for anti-inflammatory activity.
|
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
|
3.38
%
|
|
|
Antibacterial activity against Escherichia coli ATCC 25922 (CO-ADD:GN_001); MIC in CAMBH media using NBS plates, by OD(600)
|
Escherichia coli
|
-0.65
%
|
|
|
Antibacterial activity against Klebsiella pneumoniae MDR ATCC 70063 (CO-ADD:GN_003); MIC in CAMBH media using NBS plates, by OD(600)
|
Klebsiella pneumoniae
|
7.63
%
|
|
|
Antibacterial activity against Pseudomonas aeruginosa ATCC 27853 (CO-ADD:GN_042); MIC in CAMBH media using NBS plates, by OD(600)
|
Pseudomonas aeruginosa
|
9.59
%
|
|
|
Antibacterial activity against Acinetobacter baumannii ATCC 19606 (CO-ADD:GN_034); MIC in CAMBH media using NBS plates, by OD600
|
Acinetobacter baumannii
|
7.26
%
|
|
|
Antifungal activity against Candida albicans ATCC 90028 (CO-ADD:FG_001); MIC in YNB media using NBS plates, by OD630
|
Candida albicans
|
27.0
%
|
|
|
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
|
-26.65
%
|
|
|
Inhibition of human recombinant IDE expressed in Escherichia coli BL21 (DE3) cells using ATTO 655- Cys-Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-Trp as substrate at 100 uM preincubated for 10 mins followed by substrate addition and measured after 30 mins by spectrophotometric analysis relative to control
|
Homo sapiens
|
41.0
%
|
|
Journal : Eur J Med Chem
Title : Identification of ebselen as a potent inhibitor of insulin degrading enzyme by a drug repurposing screening.
Year : 2019
Volume : 179
First Page : 557
Last Page : 566
Authors : Leroux F, Bosc D, Beghyn T, Hermant P, Warenghem S, Landry V, Pottiez V, Guillaume V, Charton J, Herledan A, Urata S, Liang W, Sheng L, Tang WJ, Deprez B, Deprez-Poulain R.
Abstract : Insulin-degrading enzyme, IDE, is a metalloprotease implicated in the metabolism of key peptides such as insulin, glucagon, β-amyloid peptide. Recent studies have pointed out its broader role in the cell physiology. In order to identify new drug-like inhibitors of IDE with optimal pharmacokinetic properties to probe its multiple roles, we ran a high-throughput drug repurposing screening. Ebselen, cefmetazole and rabeprazole were identified as reversible inhibitors of IDE. Ebselen is the most potent inhibitor (IC<sub>50</sub><sub>(insulin)</sub> = 14 nM). The molecular mode of action of ebselen was investigated by biophysical methods. We show that ebselen induces the disorder of the IDE catalytic cleft, which significantly differs from the previously reported IDE inhibitors. IDE inhibition by ebselen can explain some of its reported activities in metabolism as well as in neuroprotection.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
99.38
%
|
|
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.
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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
|
-0.08
%
|
|
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
|
-0.08
%
|
|
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.
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Giardicidal activity against Giardia intestinalis incubated for 48 hrs by hemocytometric counting method
|
Giardia intestinalis
|
95.5
nM
|
|
