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Comparative Molecular Profiling of the PPARα/γ Activator Aleglitazar: PPAR Selectivity, Activity and Interaction with Cofactors
Author(s) -
Dietz Michel,
Mohr Peter,
Kuhn Bernd,
Maerki Hans Peter,
Hartman Peter,
Ruf Armin,
Benz Jörg,
Grether Uwe,
Wright Matthew B.
Publication year - 2012
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201100598
Subject(s) - nuclear receptor , peroxisome proliferator activated receptor , receptor , ppar agonist , activator (genetics) , pharmacology , cofactor , rosiglitazone , partial agonist , retinoid x receptor , chemistry , transcription factor , agonist , medicine , biology , biochemistry , gene , enzyme
Peroxisome proliferator‐activated receptors (PPARs) are a family of nuclear hormone receptors that control the expression of genes involved in a variety of physiologic processes, through heterodimerization with retinoid X receptor and complex formation with various cofactors. Drugs or treatment regimens that combine the beneficial effects of PPARα and γ agonism present an attractive therapeutic strategy to reduce cardiovascular risk factors. Aleglitazar is a dual PPARα/γ agonist currently in phase III clinical development for the treatment of patients with type 2 diabetes mellitus who recently experienced an acute coronary event. The potency and efficacy of aleglitazar was evaluated in a head‐to‐head comparison with other PPARα, γ and δ ligands. A comprehensive, 12‐concentration dose–response analysis using a cell‐based assay showed aleglitazar to be highly potent, with EC 50 values of 5 n M and 9 n M for PPARα and PPARγ, respectively. Cofactor recruitment profiles confirmed that aleglitazar is a potent and balanced activator of PPARα and γ. The efficacy and potency of aleglitazar are discussed in relation to other dual PPARα/γ agonists, in context with the published X‐ray crystal structures of both PPARα and γ.