Design and synthesis of peroxisome proliferator-activated receptor (PPAR) delta agonists and its implication to the driving force to elicit PPAR delta selectivity

Jun Ichi Kasuga, Takuji Oyama, Izumi Nakagome, Atsushi Aoyama, Kumiko Sako, Makoto Makishima, Shuichi Hirono, Kosuke Morikawa, Yuichi Hashimoto, Hiroyuki Miyachi

Research output: Contribution to journalReview articlepeer-review

2 Citations (Scopus)


A series of 3-(4-alkoxypheny) propanoic acid derivatives was prepared as candidate peroxisome proliferator-activated receptor (PPAR) δ-selective agonists, based on our previously discovered potent human PPARα/δ 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 PPARδ transactivation activity and highest PPARδ selectivity. The (5) -enantiomer of a representative compound (TIPP-204) exhibited extremely potent PPARδ transactivation activity, comparable to that of the known PPARδ-selective agonist GW-501516. To understand why TIPP-204 shows high selectivity for hPPARδ among hPPAR subtypes, and why TIPP401, a structurally related compound, is a hPPARα/δ dual agonist, computational docking of TIPP-401 to the ligand binding domains of hPPARα and hPPARδ and X-ray structure analysis of TIPP-204-hPPARδ ligand binding domain were carried out. The results allowed identification of certain amino acids as putative determinants of the hPPARδ selectivity of TIPP-204. To confirm the significance of these amino acids, GAL4-fusion proteins of mutated hPPARδs and hPPARαs 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 PPARδ-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 hPPARδ. The results revealed several interactions relevant to the hPPARδ-selectivity of the two ligands and will be useful for logical hPPARδ ligand design.

Original languageEnglish
Pages (from-to)709-718
Number of pages10
JournalYakugaku Zasshi
Issue number6
Publication statusPublished - Jun 2009
Externally publishedYes


  • Computer ligand docking
  • PPAR delta agonist
  • X-ray crystallography

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science


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