Comparative Molecular Profiling of the PPARα/γ Activator Aleglitazar: PPAR Selectivity, Activity and Interaction with Cofactors

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 PPARa and ? agonism present an attractive therapeutic strategy to reduce cardiovascular risk factors. Aleglitazar is a dual PPARa/? 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 PPARa, ? and d ligands. A comprehensive, 12-concentration doseresponse analysis using a cell-based assay showed aleglitazar to be highly potent, with EC50 values of 5 nM and 9 nM for PPARa and PPAR?, respectively. Cofactor recruitment profiles confirmed that aleglitazar is a potent and balanced activator of PPARa and ?. The efficacy and potency of aleglitazar are discussed in relation to other dual PPARa/? agonists, in context with the published X-ray crystal structures of both PPARa and ?.