Discovery of 5-aryloxy-2,4-thiazolidinediones as potent GPR40 agonists

Systematic structure–activity relationship (SAR) studies of a screening lead led to the discovery of a series of thiazolidinediones (TZDs) as potent GPR40 agonists. Among them, compound C demonstrated an acute mechanism-based glucose-lowering in an intraperitoneal glucose tolerance test (IPGTT) in l...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2010-02, Vol.20 (3), p.1298-1301
Hauptverfasser:	Zhou, Changyou, Tang, Cheng, Chang, Eric, Ge, Min, Lin, Songnian, Cline, Eric, Tan, Carina P., Feng, Yue, Zhou, Yun-Ping, Eiermann, George J., Petrov, Aleksandr, Salituro, Gino, Meinke, Peter, Mosley, Ralph, Akiyama, Taro E., Einstein, Monica, Kumar, Sanjeev, Berger, Joel, Howard, Andrew D., Thornberry, Nancy, Mills, Sander G., Yang, Lihu
Format:	Artikel
Sprache:	eng
Schlagworte:	5-Aryloxy-2,4-thiazolidinediones Agonist Animals Biological and medical sciences Diabetic Drug Discovery - methods GDIS General and cellular metabolism. Vitamins GPR40 GSIS Hypoglycemia Medical sciences Mice Mice, Knockout Pharmacology. Drug treatments Protein Binding - physiology Receptors, G-Protein-Coupled - agonists Receptors, G-Protein-Coupled - metabolism Structure-Activity Relationship Thiazolidinediones - agonists Thiazolidinediones - chemistry Thiazolidinediones - pharmacology
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Zusammenfassung:	Systematic structure–activity relationship (SAR) studies of a screening lead led to the discovery of a series of thiazolidinediones (TZDs) as potent GPR40 agonists. Among them, compound C demonstrated an acute mechanism-based glucose-lowering in an intraperitoneal glucose tolerance test (IPGTT) in lean mice, while no effects were observed in GPR40 knock-out mice. Systematic structure–activity relationship (SAR) studies of a screening lead led to the discovery of a series of thiazolidinediones (TZDs) as potent GPR40 agonists. Among them, compound C demonstrated an acute mechanism-based glucose-lowering in an intraperitoneal glucose tolerance test (IPGTT) in lean mice, while no effects were observed in GPR40 knock-out mice.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2009.10.052