7wox

Publication Abstract from PubMed

Peroxisome proliferator-activated receptor gamma (PPARgamma) antagonists are drug candidates for the treatment of type 2 diabetes, obesity, and osteoporosis. Previously, we have designed and synthesized a series of substituted phenylalkynyl amide-type PPARgamma antagonists. The representative compound, MMT-160, exhibited nanomolar-order PPARgamma antagonistic activity. To understand the antagonistic mode of action of MMT-160, mass spectrometric and X-ray crystallographic analysis of MMT-160 in the presence of the PPARgamma ligand binding domain (LBD) were performed. The mass spectrometry results clearly indicated that alkynyl amide-type PPARgamma antagonists were covalently bound to the PPARgamma LBD. The X-ray crystallographic analysis indicated that MMT-160 acted as a Michael acceptor and covalently bound to the PPARgamma LBD via Cys285. In addition, MMT-160 bound to the PPARgamma LBD with a binding mode that was different from the binding modes observed for PPARgamma agonists and partial agonists.

Arylalkynyl amide-type peroxisome proliferator-activated receptor gamma (PPARgamma)-selective antagonists covalently bind to the PPARgamma ligand binding domain with a unique binding mode.,Yoshizawa M, Aoyama T, Itoh T, Miyachi H Bioorg Med Chem Lett. 2022 May 15;64:128676. doi: 10.1016/j.bmcl.2022.128676., Epub 2022 Mar 15. PMID:35301139^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.