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 2possessing activity at these two receptors. Early availability of the crystal structure of the lead compound 2abound 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 (IC50= 1.6 nM) with partial PPARγ agonism (EC50= 212 nM, 31% max) and oral bioavailability in rat. The dual pharmacology of 2lwas demonstrated in animal models of hypertension (SHR) and insulin resistance (ZDF rat). In the SHR, 2lwas highly efficacious in lowering blood pressure, while robust lowering of glucose and triglycerides was observed in the male ZDF rat. [ABSTRACT FROM AUTHOR]