Discovery of INT131: A selective PPARI3 modulator that enhances insulin sensitivity

• Published in: Bioorganic & medicinal chemistry Vol. 21; no. 4; pp. 979 - 992
• Main Authors: Taygerly, Joshua, McGee, Lawrence, Rubenstein, Steven, Houze, Jonathan, Cushing, Timothy, Li, Yang, Motani, Alykhan, Chen, Jin-Long, Frankmoelle, Walter, Ye, Guosen, Learned, Marc, Jaen, Juan, Miao, Shichang, Timmermans, Pieter, 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: Journal Article
• Language: English
• Published: 01-02-2013
• Subjects: Diabetes mellitus
• ISSN: 0968-0896
• DOI: 10.1016/j.bmc.2012.11.058

PPARI3 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 PPARI3 modulators (SPPARI3Ms) and display a unique pharmacological profile compared to the thiazolidinedione (TZD) class of PPARI3 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 PPARI3 partial agonist that displays robust glucose-lowering activity in rodent models of diabetes while exhibiting a reduced side-effects profile compared to marketed TZDs.