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  • Title: Comparative molecular profiling of the PPARα/γ activator aleglitazar: PPAR selectivity, activity and interaction with cofactors.
    Author: Dietz M, Mohr P, Kuhn B, Maerki HP, Hartman P, Ruf A, Benz J, Grether U, Wright MB.
    Journal: ChemMedChem; 2012 Jun; 7(6):1101-11. PubMed ID: 22489042.
    Abstract:
    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 nM and 9 nM 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.
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