2. Academic Validation
  3. Discovery and Optimization of Potent GPR40 Full Agonists Containing Tricyclic Spirocycles

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

Affiliation

  • 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.
PMID: 24900707 DOI: 10.1021/ml300427u
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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