title: Design, synthesis, and evaluation of a novel series of alpha-substituted phenylpropanoic acid derivatives as human peroxisome proliferator-activated receptor (PPAR) alpha/delta dual agonists for the treatment of metabolic syndrome.
abstract: A series of alpha-alkyl-substituted phenylpropanoic acids was prepared as dual agonists of peroxisome proliferator-activated receptors alpha and delta (PPARalpha/delta). Structure-activity relationship studies indicated that the shape of the linking group and the shape of the substituent at the distal benzene ring play key roles in determining the potency and the selectivity of PPAR subtype transactivation. Structure-activity relationships among the amide series (10) and the reversed amide series (13) are similar, but not identical, especially in the case of the compounds bearing a bulky hydrophobic substituent at the distal benzene ring, indicating that the hydrophobic tail part of the molecules in these two series binds at somewhat different positions in the large binding pocket of PPAR. alpha-Alkyl-substituted phenylpropanoic acids of (S)-configuration were identified as potent human PPARalpha/delta dual agonists. Representative compounds exhibited marked nuclear receptor selectivity for PPARalpha and PPARdelta. Subtype-selective PPAR activation was also examined by analysis of the mRNA expression of PPAR-regulated genes.
authors.affiliation: Institute of Molecular and Cellular Biosciences, University of Tokyo, Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Kasuga
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yamasaki
authors.forename: Yoko
authors.initials: Y
authors.lastname: Araya
authors.forename: Aya
authors.initials: A
authors.lastname: Nakagawa
authors.forename: Makoto
authors.initials: M
authors.lastname: Makishima
authors.forename: Takefumi
authors.initials: T
authors.lastname: Doi
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hashimoto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Miyachi
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000473:pathology; D015195:Drug Design; D006801:Humans; D007668:Kidney / Q000187:drug effects; D008113:Liver Neoplasms / Q000188:drug therapy / Q000473:pathology; D024821:Metabolic Syndrome / Q000188:drug therapy*; D047493:PPAR alpha / Q000819:agonists*; D047494:PPAR delta / Q000819:agonists*; D010666:Phenylpropionates / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation / Q000187:drug effects*
chemical_list: D047493:PPAR alpha; D047494:PPAR delta; D010666:Phenylpropionates