Discovery and Optimization of Potent GPR40 Full Agonists Containing Tricyclic Spirocycles.
ACS Med Chem Lett
; 4(6): 551-5, 2013 Jun 13.
Article
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| MEDLINE
| ID: mdl-24900707
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.
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MEDLINE
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En
Revista:
ACS Med Chem Lett
Año:
2013
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Article
País de afiliación:
Estados Unidos