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

8 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

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Peroxisome Proliferator-Activated Receptors
Stereochemistry
Derivatives
Acids
Enantiomers
Carbon
In Vitro Techniques
Atoms

Keywords

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

ASJC Scopus subject areas

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

Cite this

Design, synthesis and in vitro evaluation of a series of α-substituted phenylpropanoic acid PPARγ agonists to further investigate the stereochemistry-activity relationship. / Ohashi, Masao; Nakagome, Izumi; Kasuga, Jun Ichi; Nobusada, Hiromi; Matsuno, Kenji; Makishima, Makoto; Hirono, Shuichi; Hashimoto, Yuichi; Miyachi, Hiroyuki.

In: Bioorganic and Medicinal Chemistry, Vol. 20, No. 21, 01.11.2012, p. 6375-6383.

Research output: Contribution to journalArticle

Ohashi, Masao ; Nakagome, Izumi ; Kasuga, Jun Ichi ; Nobusada, Hiromi ; Matsuno, Kenji ; Makishima, Makoto ; Hirono, Shuichi ; Hashimoto, Yuichi ; Miyachi, Hiroyuki. / Design, synthesis and in vitro evaluation of a series of α-substituted phenylpropanoic acid PPARγ agonists to further investigate the stereochemistry-activity relationship. In: Bioorganic and Medicinal Chemistry. 2012 ; Vol. 20, No. 21. pp. 6375-6383.
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