Amgen Inc. 1120 Veterans Blvd., South San Francisco, CA 94080, USA.
Bioorg Med Chem Lett. 2012 Jan 15;22(2):1267-70. doi: 10.1016/j.bmcl.2011.10.118. Epub 2011 Nov 6.
The discovery that certain long chain fatty acids potentiate glucose stimulated insulin secretion through the previously orphan receptor GPR40 sparked interest in GPR40 agonists as potential antidiabetic agents. Optimization of a series of β-substituted phenylpropanoic acids led to the identification of (S)-3-(4-((4'-(trifluoromethyl)biphenyl-3-yl)methoxy)phenyl)hex-4-ynoic acid (AMG 837) as a potent GPR40 agonist with a superior pharmacokinetic profile and robust glucose-dependent stimulation of insulin secretion in rodents.
某些长链脂肪酸通过先前被认为是孤儿受体 GPR40 来增强葡萄糖刺激的胰岛素分泌的发现，引发了人们对 GPR40 激动剂作为潜在抗糖尿病药物的兴趣。对一系列β取代的苯基丙酸酸的优化导致了（S）-3-（4-（（4'-（三氟甲基）联苯-3-基）甲氧基）苯基）己-4-炔酸（AMG 837）的鉴定，它是一种有效的 GPR40 激动剂，具有优越的药代动力学特征和在啮齿动物中强大的葡萄糖依赖性胰岛素分泌刺激作用。
