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Discovery of a series of imidazo[4,5-b]pyridines with dual activity at angiotensin II type 1 receptor and peroxisome proliferator-activated receptor-γ.

Abstract：

:Mining of an in-house collection of angiotensin II type 1 receptor antagonists to identify compounds with activity at the peroxisome proliferator-activated receptor-γ (PPARγ) 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 PPARγ confirmed the mode of interaction of this scaffold to the nuclear receptor and assisted in the optimization of PPARγ 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 (IC(50) = 1.6 nM) with partial PPARγ agonism (EC(50) = 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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Casimiro-Garcia A,Filzen GF,Flynn D,Bigge CF,Chen J,Davis JA,Dudley DA,Edmunds JJ,Esmaeil N,Geyer A,Heemstra RJ,Jalaie M,Ohren JF,Ostroski R,Ellis T,Schaum RP,Stoner C

doi

10.1021/jm200409s

subject

Has Abstract

pub_date

2011-06-23 00:00:00

pages

4219-33

issue

12

eissn

0022-2623

issn

1520-4804

journal_volume

54

pub_type

杂志文章

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