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.
Original language | English (US) |
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Pages (from-to) | 551-555 |
Number of pages | 5 |
Journal | ACS Medicinal Chemistry Letters |
Volume | 4 |
Issue number | 6 |
DOIs | |
State | Published - Jun 13 2013 |
Externally published | Yes |
Keywords
- AM-1638
- AM-5262
- AMG 837
- FFA1
- FFAR1
- Full agonist
- GPR40
- Spirocycles
- Tricyclic
ASJC Scopus subject areas
- Biochemistry
- Drug Discovery
- Organic Chemistry