title: Discovery of highly potent and selective benzyloxybenzyl-based peroxisome proliferator-activator receptor (PPAR) delta agonists.
abstract: A series of 1,4-benzyloxybenzylsulfanylaryl carboxylic acids were prepared and their activities for PPAR receptor subtypes (alpha, delta, and gamma) with potential indications for the treatment of dyslipidemia were investigated. Analog 13a displayed the greatest binding affinity (IC(50)=10nM) and selectivity (120-fold) for PPARdelta over PPARalpha. Many of the analogs investigated were found to be highly selective for PPARdelta and were dependent on the point of attachment of the substituent. In the 1,4-series, analog 28e was found to be the most potent (IC(50)=1.7 nM) and selective (>1000-fold) compound for PPARdelta. None of the compounds tested showed appreciable binding affinity for PPARgamma.
authors.affiliation: Department of Chemistry, Pfizer Global Research and Development, Michigan Laboratories, Ann Arbor, MI 48105, USA. ageyer1@gmail.com <ageyer1@gmail.com>
authors.forename: Larry D
authors.initials: LD
authors.lastname: Bratton
authors.forename: Gary F
authors.initials: GF
authors.lastname: Filzen
authors.forename: Andrew
authors.initials: A
authors.lastname: Geyer
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Hoffman
authors.forename: Gina
authors.initials: G
authors.lastname: Lu
authors.forename: Jim
authors.initials: J
authors.lastname: Pulaski
authors.forename: Bharat K
authors.initials: BK
authors.lastname: Trivedi
authors.forename: Paul C
authors.initials: PC
authors.lastname: Unangst
authors.forename: Xiangyang
authors.initials: X
authors.lastname: Xu
mesh_terms: D002264:Carboxylic Acids / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D008055:Lipids / Q000737:chemistry; D008956:Models, Chemical; D047494:PPAR delta / Q000819:agonists* / Q000737:chemistry; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000737:chemistry; D013696:Temperature
chemical_list: D002264:Carboxylic Acids; D008024:Ligands; D008055:Lipids; D047494:PPAR delta; D013438:Sulfhydryl Compounds