Discovery Research, GlaxoSmithKline Pharmaceuticals, Collegeville, PA 19426-0989, USA.
J Med Chem. 2009 Dec 24;52(24):7962-5. doi: 10.1021/jm901434t.
A series of 3-aryl-4-isoxazolecarboxamides identified from a high-throughput screening campaign as novel, potent small molecule agonists of the human TGR5 G-protein coupled receptor is described. Subsequent optimization resulted in the rapid identification of potent exemplars 6 and 7 which demonstrated improved GLP-1 secretion in vivo via an intracolonic dose coadministered with glucose challenge in a canine model. These novel TGR5 receptor agonists are potentially useful therapeutics for metabolic disorders such as type II diabetes and its associated complications.
本文描述了一系列从高通量筛选活动中鉴定出的 3-芳基-4-异噁唑甲酰胺，它们是新型强效小分子人类 TGR5 G 蛋白偶联受体激动剂。随后的优化导致了强效范例 6 和 7 的快速鉴定，它们在犬模型中通过与葡萄糖共给药的结肠内剂量给药显示出改善的 GLP-1 分泌。这些新型 TGR5 受体激动剂可能是治疗代谢紊乱的有用疗法，如 2 型糖尿病及其相关并发症。
