Structural design and synthesis of arylalkynyl amide-type peroxisome proliferator-activated receptor γ3 (PPAR γ3)-selective antagonists based on the helix12-folding inhibition hypothesis

Masao Ohashi, Kanae Gamo, Yuta Tanaka, Minoru Waki, Yoko Beniyama, Kenji Matsuno, Jun Wada, Masafumi Tenta, Jun Eguchi, Makoto Makishima, Nobuyasu Matsuura, Takuji Oyama, Hiroyuki Miyachi

Research output: Contribution to journalArticle

15 Citations (Scopus)


Peroxisome proliferator-activated receptor γ3 (PPARγ3) antagonists are candidates for treatment of type 2 diabetes, obesity and osteoporosis. However, few rational design strategies are currently available. Here, we utilized the helix12 (H12)-folding inhibition hypothesis, in combination with our previously determined X-ray crystal structure of PPARγ3 agonist MEKT-21 (6) complexed with the PPARγ3 ligand-binding domain, to design and develop a potent phenylalkynyl amide-type PPARγ3 antagonist 9i, focusing initially on pinpoint structural modification of the propanoic acid moiety of 6. Since 9i retained very weak, but distinct, PPARγ3 agonist activity, we next modified the distal benzene ring of 9i, aiming to delete the residual PPARγ3 agonist activity while retaining the antagonist activity. Introduction of a chlorine atom at the 2-position of the distal benzene ring afforded 9p, which exhibited potent, PPARγ3-selective full antagonist activity without detectable agonist activity. We found that 9p stabilized the corepressor-PPARγ3 complex and suppressed basal PPARγ3 activity. This compound showed anti-adipogenesis activity at the cellular level. This agonist-antagonist switching concept based on the H12-folding inhibition hypothesis should also be applicable for designing other classes of PPARγ3 full antagonists.

Original languageEnglish
Pages (from-to)53-67
Number of pages15
JournalEuropean Journal of Medicinal Chemistry
Publication statusPublished - Jan 27 2015


ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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