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]

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] (PPAR[gamma]) partial agonists is described. Starting from a known AT1 antagonist template, conformational re...

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Published in:Bioorganic & medicinal chemistry letters 2013-02, Vol.23 (3), p.767-772
Main Authors: Casimiro-Garcia, Agustin, Heemstra, Ronald J, Bigge, Christopher F, Chen, Jing, Ciske, Fred A, Davis, Jo Ann, Ellis, Teresa, Esmaeil, Nadia, Flynn, Declan, Han, Seungil, Jalaie, Mehran, Ohren, Jeffrey F, Powell, Noel A
Format: Article
Language:English
Subjects:
Angiotensin II
Antagonists
Crystal structure
Ionizing radiation
Nitrogen
Peroxisome proliferator-activated receptors
Pharmacology
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Summary: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] (PPAR[gamma]) 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 PPAR[gamma] was corroborated through the X-ray crystal structure of 12b bound to the human PPAR[gamma] ligand binding domain. Modulation of activity at both receptors through substitution at the pyridone nitrogen led to the identification of potent dual AT1 antagonists/PPAR[gamma] partial agonists. Among them, 21b was identified possessing potent dual pharmacology (AT1 IC50 = 7 nM; PPAR[gamma] EC50 = 295 nM, 27% max) and good ADME properties.
ISSN:0960-894X