Discovery and Optimization of Potent GPR40 Full Agonists Containing Tricyclic Spirocycles

  • ACS Med Chem Lett. 2013 May 7;4(6):551-5. doi: 10.1021/ml300427u.
Yingcai Wang  1 ,  Jiwen Jim Liu  1 ,  Paul J Dransfield  1 ,  Liusheng Zhu  1 ,  Zhongyu Wang  1 ,  Xiaohui Du  1 ,  Xianyun Jiao  1 ,  Yongli Su  1 ,  An-Rong Li  1 ,  Sean P Brown  1 ,  Annie Kasparian  1 ,  Marc Vimolratana  1 ,  Ming Yu  1 ,  Vatee Pattaropong  1 ,  Jonathan B Houze  1 ,  Gayathri Swaminath  1 ,  Thanhvien Tran  1 ,  Khanh Nguyen  1 ,  Qi Guo  1 ,  Jane Zhang  1 ,  Run Zhuang  1 ,  Frank Li  1 ,  Lynn Miao  1 ,  Michael D Bartberger  1 ,  Tiffany L Correll  1 ,  David Chow  1 ,  Simon Wong  1 ,  Jian Luo  1 ,  Daniel C-H Lin  1 ,  Julio C Medina  1
Affiliations
  • 1. Department of Therapeutic Discovery, Metabolic Disorders, Translational Sciences, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States and One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Abstract

GPR40 (FFAR1 or FFA1) is a target of high interest being pursued to treat type II diabetes due to its unique mechanism leading to little risk of Hypoglycemia. We recently reported the discovery of AM-1638 (2), a potent full agonist of GPR40. In this report, we present the discovery of GPR40 full agonists containing conformationally constrained tricyclic spirocycles and their structure-activity relationships leading to more potent agonists such as AM-5262 (26) with improved rat PK profile and general selectivity profile. AM-5262 enhanced glucose stimulated Insulin secretion (mouse and human islets) and improved glucose homeostasis in vivo (OGTT in HF/STZ mice) when compared to AM-1638.

Keywords
AM-1638; AM-5262; AMG 837; FFA1; FFAR1; GPR40; full agonist; spirocycles; tricyclic.
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