Analysis of the critical structural determinant(s) of species-selective peroxisome proliferator-activated receptor alpha (PPAR alpha)-activation by phenylpropanoic acid-type PPAR alpha agonists.
In order to identify the critical structural feature(s) of phenylpropanoic acid-type PPARalpha agonists, such as KCL, which exhibit human peroxisome proliferator-activated receptor alpha (PPARalpha)-selective activation, transient transactivation assay of KCL and related derivatives was performed with PPARalpha containing wild-type and point-mutated (I272F or T279M) ligand-binding domain. The results indicated that the interaction of the distal hydrophobic tail part of KCL and related derivatives with amino acid residue 272 (isoleucine) in the helix three region of PPARalpha is of primary importance for human-selective PPARalpha activation.
Miyachi
Hiroyuki
H
Discovery Research Laboratories, Kyorin Pharmaceutical Co., Ltd., 2399-1Mitarai, 329-0114, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan. hiroyuki.miyachi@mb.kyorin-pharm.co.jp
Uchiki
Hideharu
H
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D006801:Humans; D010666:Phenylpropionates / Q000737:chemistry* / Q000494:pharmacology*; D017354:Point Mutation; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism*; D013045:Species Specificity; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000819:agonists* / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology
D010666:Phenylpropionates; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors