Further Studies on Imidazo[4,5-b]pyridine AT1 Angiotensin II Receptor Antagonists. Effects of the Transformation of the 4-Phenylquinoline Backbone into 4-Phenylisoquinolinone or 1-Ph

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• 作者：Andrea Cappelli ; Gal.la Pericot Mohr ; Germano Giuliani ; Simone Galeazzi ; Maurizio Anzini ; Laura Mennuni ; Flora Ferrari ; Francesco Makovec ; Eva M. Kleinrath ; Thierry Langer ; Massimo Valoti ; Gianluca Gi
• 刊名：Journal of Medicinal Chemistry
• 出版年：2006
• 出版时间：November 2, 2006
• 年：2006
• 卷：49
• 期：22
• 页码：6451 - 6464
• 全文大小：737K
• 年卷期：v.49,no.22(November 2, 2006)
• ISSN：1520-4804

文摘

The 4-phenylquinoline fragment of novel AT₁ receptor antagonists 4 based on imidazo[4,5-b]pyridine moietywas replaced by 4-phenylisoquinolinone (compounds 5) or 1-phenylindene (compounds 6) scaffolds toinvestigate the structure-activity relationships. Binding studies showed that most of the synthesizedcompounds display high affinity for the AT₁ receptor. Because of the in vitro high potency of carboxylicacids 5b,f, they were evaluated in permeability (in Caco-2 cells) and in pharmacokinetic studies in comparisonwith quinoline derivatives 4b,i,j,k. The studies showed that these compounds are characterized by rapidexcretion, low membrane permeability, and low oral bioavailability. The structure optimization of the indenederivatives led to compounds 6e,f possessing interesting AT₁ receptor affinities. Optimization producedpolymerizing AT₁ receptor ligand 6c, which forms a thermoreversible polymer (poly-6c) and is releasedfrom the latter by a temperature-dependent kinetics. The results suggest the possibility of developing novelpolymeric prodrugs based on a new release mechanism. Finally, a set of 34 AT₁ receptor antagonists wasused as a new test for the evaluation of the predictive capability of the previously published qualitative andquantitative pharmacophore models.