title: 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 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.
authors.affiliation: Discovery Technologies, F. Hoffmann-La Roche AG, Grenzacherstrasse 124, Basel 4070, Switzerland.
authors.forename: Michel
authors.initials: M
authors.lastname: Dietz
authors.forename: Peter
authors.initials: P
authors.lastname: Mohr
authors.forename: Bernd
authors.initials: B
authors.lastname: Kuhn
authors.forename: Hans Peter
authors.initials: HP
authors.lastname: Maerki
authors.forename: Peter
authors.initials: P
authors.lastname: Hartman
authors.forename: Armin
authors.initials: A
authors.lastname: Ruf
authors.forename: Jörg
authors.initials: J
authors.lastname: Benz
authors.forename: Uwe
authors.initials: U
authors.lastname: Grether
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Wright
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D011345:Fenofibrate / Q000031:analogs & derivatives / Q000737:chemistry; D008024:Ligands; D008969:Molecular Sequence Data; D010080:Oxazoles / Q000737:chemistry* / Q000494:pharmacology; D047493:PPAR alpha / Q000819:agonists* / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000737:chemistry; D013876:Thiophenes / Q000737:chemistry* / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D008024:Ligands; D010080:Oxazoles; D047493:PPAR alpha; D047495:PPAR gamma; D010455:Peptides; D045162:Thiazolidinediones; D013876:Thiophenes; C542437:aleglitazar; C006012:fenofibric acid; D011345:Fenofibrate; D000077205:Pioglitazone