The Discovery, Preclinical, and Early Clinical Development of Potent and Selective GPR40 Agonists for the Treatment of Type 2 Diabetes Mellitus (LY2881835, LY2922083, and LY2922470)
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- 作者：Chafiq Hamdouchi ; Steven D. Kahl ; Anjana Patel Lewis ; Guemalli R. Cardona ; Richard W. Zink ; Keyue Chen ; Thomas E. Eessalu ; James V. Ficorilli ; Marialuisa C. Marcelo ; Keith A. Otto ; Kelly L. Wilbur ; Jayana P. Lineswala ; Jared L. Piper ; D. Scott Coffey ; Stephanie A. Sweetana ; Joseph V. Haas ; Dawn A. Brooks ; Edward J. Pratt ; Ruth M. Belin ; Mark A. Deeg ; Xiaosu Ma ; Ellen A. Cannady ; Jason T. Johnson ; Nathan P. Yumibe ; Qi Chen ; Pranab Maiti ; Chahrzad Montrose-Rafizadeh ; Yanyun Chen ; Anne Reifel Miller
- 刊名：Journal of Medicinal Chemistry
- 出版年：2016
- 出版时间：December 22, 2016
- 年：2016
- 卷：59
- 期：24
- 页码：10891-10916
- 全文大小：1620K
- ISSN：1520-4804
文摘
The G protein-coupled receptor 40 (GPR40) also known as free fatty acid receptor 1 (FFAR1) is highly expressed in pancreatic, islet β-cells and responds to endogenous fatty acids, resulting in amplification of insulin secretion only in the presence of elevated glucose levels. Hypothesis driven structural modifications to endogenous FFAs, focused on breaking planarity and reducing lipophilicity, led to the identification of spiropiperidine and tetrahydroquinoline acid derivatives as GPR40 agonists with unique pharmacology, selectivity, and pharmacokinetic properties. Compounds 1 (LY2881835), 2 (LY2922083), and 3 (LY2922470) demonstrated potent, efficacious, and durable dose-dependent reductions in glucose levels along with significant increases in insulin and GLP-1 secretion during preclinical testing. A clinical study with 3 administered to subjects with T2DM provided proof of concept of 3 as a potential glucose-lowering therapy. This manuscript summarizes the scientific rationale, medicinal chemistry, preclinical, and early development data of this new class of GPR40 agonists.