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

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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 (S)-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.

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

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