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

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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

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

J Med Chem. 2011 Jun 23;54(12):4219-33. doi: 10.1021/jm200409s. Epub 2011 May 26.

PubMed ID
21557540 [ View in PubMed
]
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-gamma (PPARgamma) 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 PPARgamma confirmed the mode of interaction of this scaffold to the nuclear receptor and assisted in the optimization of PPARgamma activity. Among the new compounds, (S)-3-(5-(2-(1H-tetrazol-5-yl)phenyl)-2,3-dihydro-1H-inden-1-yl)-2-ethyl-5-isobut yl-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 PPARgamma 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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
PioglitazonePeroxisome proliferator-activated receptor gammaEC 50 (nM)1280N/AN/ADetails
TelmisartanPeroxisome proliferator-activated receptor gammaEC 50 (nM)1520N/AN/ADetails
TelmisartanType-1 angiotensin II receptorIC 50 (nM)0.49N/AN/ADetails