PPARδ選択的アゴニストの創製と受容体-リガンド複合体構造情報を踏まえた選択性発現機構解明  [in Japanese] Design and Synthesis of Peroxisome Proliferator-activated Receptor (PPAR) Delta Agonists and Its Implication to the Driving Force to Elicit PPAR Delta Selectivity  [in Japanese]

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Author(s)

Abstract

  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 <i>n</i>-butoxy compound exhibited the most potent PPARδ transactivation activity and highest PPARδ selectivity. The (<i>S</i>)-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 TIPP-401, 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.<br>

Journal

  • YAKUGAKU ZASSHI

    YAKUGAKU ZASSHI 129(6), 709-718, 2009

    The Pharmaceutical Society of Japan

Codes

  • NII Article ID (NAID)
    130000136176
  • NII NACSIS-CAT ID (NCID)
    AN00284903
  • Text Lang
    JPN
  • ISSN
    0031-6903
  • NDL Article ID
    10328993
  • NDL Source Classification
    ZS51(科学技術--薬学)
  • NDL Call No.
    Z19-411
  • Data Source
    NDL  J-STAGE 
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