Design, synthesis, and evaluation of imidazo[4,5-c]pyridin-4-one derivatives with dual activity at angiotensin II type 1 receptor and peroxisome proliferator-activated receptor-gamma.

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Casimiro-Garcia A, Heemstra RJ, Bigge CF, Chen J, Ciske FA, Davis JA, Ellis T, Esmaeil N, Flynn D, Han S, Jalaie M, Ohren JF, Powell NA

Design, synthesis, and evaluation of imidazo[4,5-c]pyridin-4-one derivatives with dual activity at angiotensin II type 1 receptor and peroxisome proliferator-activated receptor-gamma.

Bioorg Med Chem Lett. 2013 Feb 1;23(3):767-72. doi: 10.1016/j.bmcl.2012.11.088. Epub 2012 Dec 1.

PubMed ID
23265881 [ View in PubMed
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Abstract

Identification of a series of imidazo[4,5-c]pyridin-4-one derivatives that act as dual angiotensin II type 1 (AT1) receptor antagonists and peroxisome proliferator-activated receptor-gamma (PPARgamma) partial agonists is described. Starting from a known AT1 antagonist template, conformational restriction was introduced by incorporation of an indane ring that when combined with appropriate substitution at the imidazo[4,5-c]pyridin-4-one provided novel series 5 possessing the desired dual activity. The mode of interaction of this series with PPARgamma was corroborated through the X-ray crystal structure of 12b bound to the human PPARgamma ligand binding domain. Modulation of activity at both receptors through substitution at the pyridone nitrogen led to the identification of potent dual AT1 antagonists/PPARgamma partial agonists. Among them, 21b was identified possessing potent dual pharmacology (AT1 IC(50) = 7 nM; PPARgamma EC(50) = 295 nM, 27% max) and good ADME properties.

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