Discovery of INT131: A selective PPAR[gamma] modulator that enhances insulin sensitivity

PPAR[gamma] 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 PPAR[gamma] modulators (SPPAR[gamma]Ms) and display...

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Published in:Bioorganic & medicinal chemistry 2013-02, Vol.21 (4), p.979-992
Main Authors: Taygerly, Joshua P, McGee, Lawrence R, Rubenstein, Steven M, Houze, Jonathan B, Cushing, Timothy D, Li, Yang, Motani, Alykhan, Chen, Jin-Long, Frankmoelle, Walter, Ye, Guosen, Learned, Marc R, Jaen, Juan, Miao, Shichang, Timmermans, Pieter B, Thoolen, Martin, Kearney, Patrick, Flygare, John, Beckmann, Holger, Weiszmann, Jennifer, Lindstrom, Michelle, Walker, Nigel, Liu, Jinsong, Biermann, Donna, Wang, Zhulun, Hagiwara, Atsushi, Iida, Tetsuya, Aramaki, Hisateru, Kitao, Yuki, Shinkai, Hisashi, Furukawa, Noboru, Nishiu, Jun, Nakamura, Motonao
Format: Article
Language:English
Subjects:
Diabetes mellitus
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Summary:PPAR[gamma] 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 PPAR[gamma] modulators (SPPAR[gamma]Ms) and display a unique pharmacological profile compared to the thiazolidinedione (TZD) class of PPAR[gamma] 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 PPAR[gamma] partial agonist that displays robust glucose-lowering activity in rodent models of diabetes while exhibiting a reduced side-effects profile compared to marketed TZDs.
ISSN:0968-0896