一种口服有效的GPR40/FFAR1受体激动剂的鉴定。
Identification of an Orally Efficacious GPR40/FFAR1 Receptor Agonist.
作者信息
Agarwal Sameer, Sasane Santosh, Deshmukh Prashant, Rami Bhadresh, Bandyopadhyay Debdutta, Giri Poonam, Giri Suresh, Jain Mukul, Desai Ranjit C
机构信息
Zydus Research Centre, Cadila Healthcare Ltd. , Sarkhej-Bavla N.H. No. 8 A, Moraiya, Ahmedabad-382 210, India.
出版信息
ACS Med Chem Lett. 2016 Sep 21;7(12):1134-1138. doi: 10.1021/acsmedchemlett.6b00331. eCollection 2016 Dec 8.
Abstract
GPR40/FFAR1 is a G protein-coupled receptor predominantly expressed in pancreatic β-cells and activated by long-chain free fatty acids, mediating enhancement of glucose-stimulated insulin secretion. A novel series of substituted 3-(4-aryloxyaryl)propanoic acid derivatives were prepared and evaluated for their activities as GPR40 agonists, leading to the identification of compound , which is highly potent in assays and exhibits robust glucose lowering effects during an oral glucose tolerance test in nSTZ Wistar rat model of diabetes (ED = 0.8 mg/kg; ED = 3.1 mg/kg) with excellent pharmacokinetic profile, and devoid of cytochromes P450 isoform inhibitory activity.
摘要
GPR40/FFAR1是一种主要在胰腺β细胞中表达的G蛋白偶联受体，可被长链游离脂肪酸激活，介导葡萄糖刺激的胰岛素分泌增强。制备了一系列新型的取代3-(4-芳氧基芳基)丙酸衍生物，并评估了它们作为GPR40激动剂的活性，从而鉴定出化合物 ，该化合物在 试验中具有高效能，并且在糖尿病nSTZ Wistar大鼠模型的口服葡萄糖耐量试验中表现出强大的降糖作用（ED = 0.8 mg/kg；ED = 3.1 mg/kg），具有优异的药代动力学特征，且不具有细胞色素P450同工酶抑制活性。
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