Document Detail

Design and synthesis of peroxisome proliferator-activated receptor (PPAR) delta agonists and its implication to the driving force to elicit PPAR delta selectivity
MedLine Citation:
PMID:  19483413     Owner:  NLM     Status:  MEDLINE    
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.
Jun-Ichi Kasuga; Takuji Oyama; Izumi Nakagome; Atsushi Aoyama; Kumiko Sako; Makoto Makishima; Shuichi Hirono; Kosuke Morikawa; Yuichi Hashimoto; Hiroyuki Miyachi
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Publication Detail:
Type:  English Abstract; Journal Article; Review    
Journal Detail:
Title:  Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan     Volume:  129     ISSN:  0031-6903     ISO Abbreviation:  Yakugaku Zasshi     Publication Date:  2009 Jun 
Date Detail:
Created Date:  2009-06-01     Completed Date:  2009-08-06     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0413613     Medline TA:  Yakugaku Zasshi     Country:  Japan    
Other Details:
Languages:  jpn     Pagination:  709-18     Citation Subset:  IM    
Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo, Japan.
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MeSH Terms
Butyric Acids / chemical synthesis*,  chemistry,  pharmacology*
Crystallography, X-Ray
Drug Design*
Hydrocarbons, Fluorinated / chemical synthesis*,  chemistry,  pharmacology*
PPAR delta / agonists*
Structure-Activity Relationship
Reg. No./Substance:
0/Butyric Acids; 0/Hydrocarbons, Fluorinated; 0/Ligands; 0/PPAR delta; 0/TIPP-204; 0/TIPP-401

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