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

J.P. Taygerly, L.R. McGee, S.M. Rubenstein, J.B. Houze, T.D. Cushing, Y. Li, A. Motani, J-L. Chen, W. Frankmoelle, G. Ye, M.R. Learned, J. Jaen, S. Miao, P.B. Timmermans, M. Thoolen, P. Kearney, J. Flygare, H. Beckmann, J. Weiszmann, M. Lindstrom, N. Walker, J. Liu, D. Biermann, Z. Wang, A. Hagiwara, T. Iida, H. Aramaki, Y. Kitao, H. Shinkai, N. Furukawa, J. Nishiu, and M. Nakamura

ABSTRACT:  PPARg is a member of the nuclear hormone receptor family and has been shown to have a key role in the regulation of glucose homeostasis.  This paper describes the discovery of a novel chemical class of diarylsulfonamide partial agonists that act as selective PPARg modulators (SPPARgMs) and display a unique pharmacological profile compared to the thiazolidinedione (TZD) class of PPARg 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 PPARg partial agonist that displays robust glucose-lowering activity in rodent models of diabetes while exhibiting a reduced side-effect profile compared to marketed TZDs.

Bioorganic & Medicinal Chem.

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