title: [Design and synthesis of peroxisome proliferator-activated receptor (PPAR) delta agonists and its implication to the driving force to elicit PPAR delta selectivity].
abstract: A series of 3-(4-alkoxypheny)propanoic acid derivatives was prepared as candidate peroxisome proliferator-activated receptor (PPAR) delta-selective agonists, based on our previously discovered potent human PPARalpha/delta dual agonist TIPP-401 as a lead compound. Structure-activity relationship studies clearly indicated the importance of the chain length of the alkoxy group at the 4-position, and the n-butoxy compound exhibited the most potent PPARdelta transactivation activity and highest PPARdelta selectivity. The (S)-enantiomer of a representative compound (TIPP-204) exhibited extremely potent PPARdelta transactivation activity, comparable to that of the known PPARdelta-selective agonist GW-501516. To understand why TIPP-204 shows high selectivity for hPPARdelta among hPPAR subtypes, and why TIPP-401, a structurally related compound, is a hPPARalpha/delta dual agonist, computational docking of TIPP-401 to the ligand binding domains of hPPARalpha and hPPARdelta and X-ray structure analysis of TIPP-204-hPPARdelta ligand binding domain were carried out. The results allowed identification of certain amino acids as putative determinants of the hPPARdelta selectivity of TIPP-204. To confirm the significance of these amino acids, GAL4-fusion proteins of mutated hPPARdeltas and hPPARalphas were prepared, and the transactivation activity of TIPP-204 toward the mutants was evaluated. The amino acid(s) that predominantly influence the potency and selectivity of TIPP-204 are different from that of the well-known PPARdelta-selective agonist GW-501516, which belongs to a different chemical class. The significance of these amino acids was confirmed by the examination of the complex structure between TIPP-204 and hPPARdelta. The results revealed several interactions relevant to the hPPARdelta-selectivity of the two ligands and will be useful for logical hPPARdelta ligand design.
authors.affiliation: Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo, Japan.
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Kasuga
authors.forename: Takuji
authors.initials: T
authors.lastname: Oyama
authors.forename: Izumi
authors.initials: I
authors.lastname: Nakagome
authors.forename: Atsushi
authors.initials: A
authors.lastname: Aoyama
authors.forename: Kumiko
authors.initials: K
authors.lastname: Sako
authors.forename: Makoto
authors.initials: M
authors.lastname: Makishima
authors.forename: Shuichi
authors.initials: S
authors.lastname: Hirono
authors.forename: Kosuke
authors.initials: K
authors.lastname: Morikawa
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hashimoto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Miyachi
mesh_terms: D002087:Butyrates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D015195:Drug Design; D006845:Hydrocarbons, Fluorinated / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D047494:PPAR delta / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D002087:Butyrates; D006845:Hydrocarbons, Fluorinated; D008024:Ligands; D047494:PPAR delta; C542588:TIPP-204; C522376:TIPP-401