Design and Synthesis of Peroxisome Proliferator-activated Receptor (PPAR) Gamma Antagonists Based on the Principle of Operation of Nuclear Receptor I.

Peroxisome proliferator-activated receptor γ (PPARγ) antagonist is a molecular target to create drug for the treatment of not only type 2 diabetes and obesity, but also cancer. However, few rational drug design strategies and concepts are available. Here, we utilized the nuclear receptor helix12-folding inhibition hypothesis, in combination with structural biology data of our PPARγ agonist (5) complexed with the PPARγ ligand-binding domain. We found a potent phenylalkynyl amide-type PPARγ antagonist 18i, based on pinpoint structural modification of the acidic head part of 5. Although 18i exhibited potent PPARγ antagonistic activity, it retained very weak, but distinct PPARγ agonistic activity. We then modified the distal benzene ring of 18i, to delete the residual PPARγ agonistic activity. Introduction of a chlorine atom at the 2-position of the distal benzene ring afforded 18p, which exhibited potent, PPARγ-selective antagonistic activity without any detectable PPARγ agonistic activity. We realized that 18p stabilized the corepressor-PPARγ complex and suppressed basal PPARγ activity. This compound showed potent anti-adipogenesis activity at the cellular level.