Structure-Activity Relationship of 2,4-Dichloro-N-(3,5-dichloro-4-(quinolin-3-yloxy)phenyl)benzenesulfonamide (INT131) Analogs for PPARγ-Targeted Antidiabetics
Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor central to fatty acid and glucose homeostasis. PPARγ is the molecular target for type 2 diabetes mellitus (T2DM) therapeutics TZDs (thiazolidinediones), full agonists of PPARγ with
Frkic, Rebecca L.,He, Yuanjun,Rodriguez, Beatriz B.,Chang, Mi Ra,Kuruvilla, Dana,Ciesla, Anthony,Abell, Andrew D.,Kamenecka, Theodore M.,Griffin, Patrick R.,Bruning, John B.
Discovery of INT131: A selective PPARγ modulator that enhances insulin sensitivity
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.
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
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(2013/03/28)
SALTS AND POLYMORPHS OF A POTENT ANTIDIABETIC COMPOUND
Salts and polymorphs of a compound useful in the treatment of inflammatory and metabolic conditions and diseases are provided herein. In particular, the invention provides salts and polymorphs of a compound which modulates the expression and/or function of a peroxisome proliferator-activated receptor. The salts and polymorphs are useful for the treatment or prevention of conditions and disorders associated with energy homeostasis such as type II diabetes, lipid metabolism, adipocyte differentiation and inflammation.
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(2008/06/13)
Therapeutic modulation of PPARgamma activity
Modulators of PPARγ activity are used in methods of treating and/or preventing conditions such as osteoporosis, Alzheimer's disease, psoriasis and acne, and cancer.
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Page/Page column 63
(2010/02/14)
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