Discovery of INT131: A selective PPAR¦Ã modulator that enhances insulin sensitivity

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• 作者：Joshua P. Taygerly^a ; ^{josh.taygerly@gmail.com} ; ^{taygerly@amgen.com} ; Lawrence R. McGee^a ; Steven M. Rubenstein^a ; Jonathan B. Houze^a ; Timothy D. Cushing^a ; Yang Li^a ; Alykhan Motani^a ; Jin-Long Chen^a ; ^&dagger ; ; Walter Frankmoelle^a ; Guosen Ye^a ; ^&Dagger ; ; Marc R. Learned^a ; ^&dagger ; ; Juan Jaen^a ; ^§ ; ; Shichang Miao^a ; ^§ ; ; Pieter B. Timmermans^a ; Martin Thoolen^a ; ^¶ ; ; Patrick Kearney^a ; John Flygare^a ; ^¡¬ ; Holger Beckmann^a ; Jennifer Weiszmann^a ; Michelle Lindstrom^a ; Nigel Walker^a ; Jinsong Liu^a ; Donna Biermann^a ; Zhulun Wang^a ; Atsushi Hagiwara^b ; Tetsuya Iida^b ; Hisateru Aramaki^b ; Yuki Kitao^b ; Hisashi Shinkai^b ; Noboru Furukawa^b ; Jun Nishiu^b ; Motonao Nakamura^b ; ^&dagger ; &dagger ;
• 关键词：INT131 ; PPAR¦Ã ; Type 2 diabetes ; Selective PPAR¦Ã modulator ; SPPAR¦ÃMs
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2013
• 出版时间：15 February, 2013
• 年：2013
• 卷：21
• 期：4
• 页码：979-992
• 全文大小：2010 K

文摘

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