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. 2013 May 7;4(6):551-5.
doi: 10.1021/ml300427u. eCollection 2013 Jun 13.

Discovery and Optimization of Potent GPR40 Full Agonists Containing Tricyclic Spirocycles

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

Discovery and Optimization of Potent GPR40 Full Agonists Containing Tricyclic Spirocycles

Yingcai Wang et al. ACS Med Chem Lett. .

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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Figures

Figure 1
Figure 1
GPR40 partial agonist AMG 837 and full agonist AM-1638.
Scheme 1
Scheme 1
Scheme 2
Scheme 2
Figure 2
Figure 2
Binding of AM-5262 was examined in cross-interaction experiments with [3H] AMG 837 (A) and [3H] AM-1638 (B). Data are expressed as cpm specific binding and shown as means ± SEM of 2–3 independent experiments. The curves are fitted to an allosteric ternary complex model.
Figure 3
Figure 3
Characterization of AM-5262 activity in isolated primary cells. Stimulation of (A) GLP-1 and (B) GIP secretion by AM-1638 and AM-5262 from rat fetal intestinal cells. Potentiation of glucose-dependent insulin secretion from (C) mouse and (D) human islets in response to indicated treatments.
Figure 4
Figure 4
AM-5262 improves glucose metabolism in high-fat fed/STZ treated mice. (A) Glucose and (B) insulin levels during an OGTT in response to treatments indicated in the figure legends. Compounds were dosed orally at −60 min, and oral glucose was administered at 0 min. (C) Total (bound + free) drug levels in the plasma 1 h post-drug dose during the OGTT.
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