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
  • 1. Amgen, Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA. [email protected]
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.