2. Academic Validation
  3. Discovery of INT131: a selective PPARγ modulator that enhances insulin sensitivity

Discovery of INT131: a selective PPARγ modulator that enhances insulin sensitivity

  • Bioorg Med Chem. 2013 Feb 15;21(4):979-92. doi: 10.1016/j.bmc.2012.11.058.
Joshua P Taygerly 1,  Lawrence R McGee,  Steven M Rubenstein,  Jonathan B Houze,  Timothy D Cushing,  Yang Li,  Alykhan Motani,  Jin-Long Chen,  Walter Frankmoelle,  Guosen Ye,  Marc R Learned,  Juan Jaen,  Shichang Miao,  Pieter B Timmermans,  Martin Thoolen,  Patrick Kearney,  John Flygare,  Holger Beckmann,  Jennifer Weiszmann,  Michelle Lindstrom,  Nigel Walker,  Jinsong Liu,  Donna Biermann,  Zhulun Wang,  Atsushi Hagiwara,  Tetsuya Iida,  Hisateru Aramaki,  Yuki Kitao,  Hisashi Shinkai,  Noboru Furukawa,  Jun Nishiu,  Motonao Nakamura
Affiliations

Affiliation

  • 1 Amgen, Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA. josh.taygerly@gmail.com
PMID: 23294830 DOI: 10.1016/j.bmc.2012.11.058
Abstract

PPARγ is a member of the nuclear hormone receptor family and plays a key role in the regulation of glucose homeostasis. This Letter describes the discovery of a novel chemical class of diarylsulfonamide partial agonists that act as selective PPARγ modulators (SPPARγMs) and display a unique pharmacological profile compared to the thiazolidinedione (TZD) class of PPARγ full agonists. Herein we report the initial discovery of partial agonist 4 and the structure-activity relationship studies that led to the selection of clinical compound INT131 (3), a potent PPARγ partial agonist that displays robust glucose-lowering activity in rodent models of diabetes while exhibiting a reduced side-effects profile compared to marketed TZDs.

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