Discovery and optimization of potent GPR40 full agonists containing tricyclic spirocycles

Yingcai Wang, Jiwen Liu, Paul J. Dransfield, Liusheng Zhu, Zhongyu Wang, Xiaohui Du, Xianyun Jiao, Yongli Su, An Rong Li, Sean P. Brown, Annie Kasparian, Marc Vimolratana, Ming Yu, Vatee Pattaropong, Jonathan B. Houze, Gayathri Swaminath, Thanhvien Tran, Khanh Nguyen, Qi Guo, Jane ZhangRun Zhuang, Frank Li, Lynn Miao, Michael D. Bartberger, Tiffany L. Correll, David Chow, Simon Wong, Jian Luo, Daniel C.H. Lin, Julio C. Medina

Research output: Contribution to journalArticlepeer-review

72 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)551-555
Number of pages5
JournalACS Medicinal Chemistry Letters
Issue number6
StatePublished - Jun 13 2013
Externally publishedYes


  • AM-1638
  • AM-5262
  • AMG 837
  • FFA1
  • FFAR1
  • Full agonist
  • GPR40
  • Spirocycles
  • Tricyclic

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry


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