Design, Synthesis, and Evaluation of Novel and Selective G-protein Coupled Receptor 120 (GPR120) Spirocyclic Agonists

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• 作者：Jason M. CoxHong D. Chu ; Mariappan V. Chelliah ; John S. Debenham ; Keith EagenPing Lan ; Matthew Lombardo ; Clare London ; Michael A. Plotkin ; Unmesh Shah ; Zhongxiang Sun ; Henry M. Vaccaro ; Srikanth Venkatraman ; Takao Suzuki ; Nengxue Wang ; Eric R. Ashley ; Alejandro Crespo ; Maria MadeiraDennis H. Leung ; Candice Alleyne ; Aimie M. Ogawa ; Sarah Souza ; Brande Thomas-Fowlkes ; Jerry Di Salvo ; Adam Weinglass ; Melissa Kirkland ; Michele Pachanski ; Mary Ann Powles ; Effie Tozzo ; Taro E. Akiyama ; Feroze Ujjainwalla ; James R. Tata ; Christopher J. Sinz
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2017
• 出版时间：January 12, 2017
• 年：2017
• 卷：8
• 期：1
• 页码：49-54
• 全文大小：475K
• ISSN：1948-5875

文摘

Type 2 diabetes mellitus (T2DM) is an ever increasing worldwide epidemic, and the identification of safe and effective insulin sensitizers, absent of weight gain, has been a long-standing goal of diabetes research. G-protein coupled receptor 120 (GPR120) has recently emerged as a potential therapeutic target for treating T2DM. Natural occurring, and more recently, synthetic agonists have been associated with insulin sensitizing, anti-inflammatory, and fat metabolism effects. Herein we describe the design, synthesis, and evaluation of a novel spirocyclic GPR120 agonist series, which culminated in the discovery of potent and selective agonist 14. Furthermore, compound 14 was evaluated in vivo and demonstrated acute glucose lowering in an oral glucose tolerance test (oGTT), as well as improvements in homeostatic measurement assessment of insulin resistance (HOMA-IR; a surrogate marker for insulin sensitization) and an increase in glucose infusion rate (GIR) during a hyperinsulinemic euglycemic clamp in diet-induced obese (DIO) mice.