Discovery and Optimization of Potent GPR40 Full Agonists Containing Tricyclic Spirocycles
摘要:
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. 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.,
[EN] BENZOFURAN AND BENZOTHIOPHENE DERIVATIVES USEFUL IN THE TREATMENT OF HYPER-PROLIFERATIVE DISORDERS [FR] DERIVES DE BENZOFURANE ET DE BENZOTHIOPHENE UTILISES DANS LE TRAITEMENT DE TROUBLES HYPERPROLIFERATIFS
<i>O</i>-Acetyl Oximes as Transformable Directing Groups for Pd-Catalyzed C−H Bond Functionalization
作者:Sharon R. Neufeldt、Melanie S. Sanford
DOI:10.1021/ol902720d
日期:2010.2.5
O-Acetyl oximes serve as effective directing groups for Pd-catalyzed sp(2) and sp(3) C-H functionalization reactions. The C-H functionalization products can be subsequently transformed into ortho- or beta-functionalized ketones, alcohols, amines, and heterocycles.