Design, synthesis and in vitro evaluation of a series of α-substituted phenylpropanoic acid PPARγ agonists to further investigate the stereochemistry-activity relationship

Masao Ohashi, Izumi Nakagome, Jun Ichi Kasuga, Hiromi Nobusada, Kenji Matsuno, Makoto Makishima, Shuichi Hirono, Yuichi Hashimoto, Hiroyuki Miyachi

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

We previously demonstrated that the α-benzylphenylpropanoic acid-type PPARγ-selective agonist 6 exhibited a reversed stereochemistry-activity relationship, that is, the (R)-enantiomer is a more potent PPARγ agonist than the (S)-enantiomer, compared with structurally similar α- ethylphenylpropanoic acid-type PPAR agonists. Here, we designed, synthesized and evaluated the optically active α-cyclohexylmethylphenylpropanoic acid derivatives 7 and α-phenethylphenylpropanoic acid derivatives 8, respectively. Interestingly, α-cyclohexylmethyl derivatives showed reversal of the stereochemistry-activity relationship [i.e., (R) more potent than (S)], like α-benzyl derivatives, whereas α-phenethyl derivatives showed the 'normal' relationship [(S) more potent than (R)]. These results suggested that the presence of a branched carbon atom at the β-position with respect to the carboxyl group is a critical determinant of the reversed stereochemistry-activity relationship.

Original languageEnglish
Pages (from-to)6375-6383
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume20
Issue number21
DOIs
Publication statusPublished - Nov 1 2012

Keywords

  • PPAR
  • PPARγ
  • Peroxisome proliferator-activated receptor
  • Phenylpropanoic acid
  • SAR

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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