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

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Taygerly JP, McGee LR, Rubenstein SM, Houze JB, Cushing TD, Li Y, Motani A, Chen JL, Frankmoelle W, Ye G, Learned MR, Jaen J, Miao S, Timmermans PB, Thoolen M, Kearney P, Flygare J, Beckmann H, Weiszmann J, Lindstrom M, Walker N, Liu J, Biermann D, Wang Z, Hagiwara A, Iida T, Aramaki H, Kitao Y, Shinkai H, Furukawa N, Nishiu J, Nakamura M

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

Bioorg Med Chem. 2013 Feb 15;21(4):979-92. doi: 10.1016/j.bmc.2012.11.058. Epub 2012 Dec 10.

PubMed ID

23294830 [ View in PubMed

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Abstract

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

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Rosiglitazone	Peroxisome proliferator-activated receptor gamma	IC 50 (nM)	200	N/A	N/A	Details
Rosiglitazone	Peroxisome proliferator-activated receptor gamma	EC 50 (nM)	100	N/A	N/A	Details
Rosiglitazone	Peroxisome proliferator-activated receptor gamma	Ki (nM)	10	N/A	N/A	Details