Discovery of a Series of Imidazo[4,5-b]pyridines with Dual Activity at Angiotensin II Type 1 Receptor and Peroxisome Proliferator-Activated Receptor-纬

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• 作者：Agustin Casimiro-Garcia ; Gary F. Filzen ; Declan Flynn ; Christopher F. Bigge ; Jing Chen ; Jo Ann Davis ; Danette A. Dudley ; Jeremy J. Edmunds ; Nadia Esmaeil ; Andrew Geyer ; Ronald J. Heemstra ; Mehran Jalaie ; Jeffrey F. Ohren ; Robert Ostroski ; Teresa Ellis ; Robert P. Schaum ; Chad Stoner
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：June 23, 2011
• 年：2011
• 卷：54
• 期：12
• 页码：4219-4233
• 全文大小：1173K
• 年卷期：v.54,no.12(June 23, 2011)
• ISSN：1520-4804

文摘

Mining of an in-house collection of angiotensin II type 1 receptor antagonists to identify compounds with activity at the peroxisome proliferator-activated receptor-纬 (PPAR纬) revealed a new series of imidazo[4,5-b]pyridines 2 possessing activity at these two receptors. Early availability of the crystal structure of the lead compound 2a bound to the ligand binding domain of human PPAR纬 confirmed the mode of interaction of this scaffold to the nuclear receptor and assisted in the optimization of PPAR纬 activity. Among the new compounds, (S)-3-(5-(2-(1H-tetrazol-5-yl)phenyl)-2,3-dihydro-1H-inden-1-yl)-2-ethyl-5-isobutyl-7-methyl-3H-imidazo[4,5-b]pyridine (2l) was identified as a potent angiotensin II type I receptor blocker (IC₅₀ = 1.6 nM) with partial PPAR纬 agonism (EC₅₀ = 212 nM, 31% max) and oral bioavailability in rat. The dual pharmacology of 2l was demonstrated in animal models of hypertension (SHR) and insulin resistance (ZDF rat). In the SHR, 2l was highly efficacious in lowering blood pressure, while robust lowering of glucose and triglycerides was observed in the male ZDF rat.