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

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 EC₅₀ 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.