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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The synthesis and pharmacological activity of new nonpeptide angiotensin II (AII) receptor antagonists are presented. These [1,2,4]-triazolo[1,5-c]pyrimidine and 1,2,4-triazolo[4,3-c]pyrimidine derivatives represent a new class of bicyclic antagonists that produced a potent, oral antihypertensive activity in the renal artery-ligated rat model. In vitro, they displayed a high affinity for rat adrenal AII receptors and were found to be specific for the AT1 receptor subtype. A SAR study has shown the importance of the 8-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl for oral activity and the critical role of alkyl substituents at 5- and 7-positions. No significant differences were found between the [1,5-c] and [4,3-c]series. UP 269-6 (5-methyl-7-n-propyl-8-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl ]- [1,2,4]-triazolo[1,5-c]pyrimidin-2(3H)-one, derivative 29) was selected as the lead compound. It was shown to be a highly potent antihypertensive derivative (decrease in mean arterial pressure of 39.6 +/- 7.2 mmHg at 1 mg/kg po in renal artery-ligated rat) with a long duration of action which displayed a high affinity for adrenal AII receptors with a marked selectivity for the AT1 receptor subtype (Ki AT1 = 24 nM; Ki AT2 = 79,200 nM). This compound is currently undergoing extensive pharmacological and clinical development.
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PMID:Synthesis and SAR studies of novel triazolopyrimidine derivatives as potent, orally active angiotensin II receptor antagonists. 805 85

The availability of peptide and non-peptide Ang II receptor antagonists has permitted the study of Ang II receptor heterogeneity. It is now widely recognized that there are at least two distinct Ang II receptor subtypes. AT1 receptors are selective in their recognition of agents such as losartan, DuP 532, L-158,809, SK&F108566, and similar non-peptides. To date, all of the well-known actions of Ang II in mammals are blocked by the AT1 selective antagonists such as losartan and are thus designated as being mediated by the AT1 receptor. Although there have been reports of functional activity mediated through AT2 sites, the pharmacological role for the AT2 receptor has not yet been elucidated. Herein, we report the chemistry and SAR on a novel series of 1,2,3,4-tetrahydrosioquinoline-3-carboxylic acids which have selective affinity for AT2 receptors. The most potent of which (19) has an IC50 of 30 nM for the AT2 receptor in the rat adrenal radioligand binding assay.
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PMID:A novel series of selective, non-peptide inhibitors of angiotensin II binding to the AT2 site. 825 20

The synthesis and the SAR study of imidazo[4,5-b]pyridine biphenyl sulfonylureas and -carbamates as highly potent AT1-selective ANG II receptor antagonists are described. Several members of this new class of antagonists efficiently inhibited the ANG II-induced pressor response in pithed rats after iv and intraduodenal (id) administration.
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PMID:3N-methylbiphenylsulfonylurea and -carbamate substituted imidazo[4,5-b]pyridines. Potent antagonists of the ANG II AT1 receptors. 915 65

In this study we designed novel substituted benzimidazole derivatives and predicted their absorption, distribution, metabolism, excretion and toxicity (ADMET) properties, based on a predictive 3D QSAR study on 132 substituted benzimidazoles as AngII-AT1 receptor antagonists. The two best predicted compounds were synthesized and evaluated for AngII-AT1 receptor antagonism. Three different alignment tools for comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were used. The best 3D QSAR models were obtained using the rigid body (Distill) alignment method. CoMFA and CoMSIA models were found to be statistically significant with leave-one-out correlation coefficients (q(2)) of 0.630 and 0.623, respectively, cross-validated coefficients (r(2)cv) of 0.651 and 0.630, respectively, and conventional coefficients of determination (r(2)) of 0.848 and 0.843, respectively. 3D QSAR models were validated using a test set of 24 compounds, giving satisfactory predicted results (r(2)pred) of 0.727 and 0.689 for the CoMFA and CoMSIA models, respectively. We have identified some key features in substituted benzimidazole derivatives, such as lipophilicity and H-bonding at the 2- and 5-positions of the benzimidazole nucleus, respectively, for AT1 receptor antagonistic activity. We designed 20 novel substituted benzimidazole derivatives and predicted their activity. In silico ADMET properties were also predicted for these designed molecules. Finally, the compounds with best predicted activity were synthesized and evaluated for in vitro angiotensin II-AT1 receptor antagonism.
SAR QSAR Environ Res 2014
PMID:Design, synthesis, pharmacological evaluation and in silico ADMET prediction of novel substituted benzimidazole derivatives as angiotensin II-AT1 receptor antagonists based on predictive 3D QSAR models. 2459 6