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 <i>in vivoi> 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.