Discovery and Optimization of Potent GPR40 Full Agonists
Containing Tricyclic Spirocycles
- Publication date
- Publisher
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
(<b>2</b>), 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 (<b>26</b>) 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