Discovery of TAK-875: A Potent, Selective, and Orally Bioavailable GPR40 Agonist
Discovery of TAK-875: A Potent, Selective, and Orally Bioavailable GPR40 Agonist
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DOI：
10.1021/ml1000855
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发表时间：
2010-09-01
影响因子：
4.2
通讯作者：
Momose, Yu
中科院分区：
文献类型：
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作者：
Negoro, Nobuyuki;Sasaki, Shinobu;Momose, Yu
GPR 40是主要在胰腺β细胞中表达的G蛋白偶联受体之一，通过游离脂肪酸介导葡萄糖刺激的胰岛素分泌的增强。一种有效的选择性GPR 40激动剂理论上是一种安全有效的抗糖尿病药物，几乎没有或没有低血糖的风险。先导化合物I的苯丙酸部分的环化产生具有有利的体外激动剂活性和药代动力学特征的稠合的苯基链烷酸。进一步优化导致发现二氢苯并呋喃衍生物9a（[（3S）-6-（{2 '，6'-二甲基-4 '-[3-（甲基磺酰基）丙氧基]联苯-3-基}甲氧基）-2，3-二氢-1-苯并呋喃-3-基]乙酸半水合物，TAK-875）是一种强效、选择性和口服生物可利用的GPR 40激动剂，其药代动力学特征可实现长效药物疗效。在口服葡萄糖耐量受损的雌性Wistar肥胖大鼠的葡萄糖耐量试验中，化合物9a显示出有效的血浆葡萄糖降低作用和促胰岛素作用。化合物9a目前正处于治疗2型糖尿病的临床试验中。
GPR40, one of the G protein-coupled receptors predominantly expressed in pancreatic beta-cells, mediates enhancement of glucose-stimulated insulin secretion by free fatty acids. A potent and selective GPR40 agonist is theorized to be a safe and effective antidiabetic drug with little or no risk of hypoglycemia. Cyclization of the phenylpropanoic acid moiety of lead compound I produced fused phenylalkanoic acids with favorable in vitro agonist activities and pharmacokinetic profiles. Further optimization led to the discovery of dihydrobenzofuran derivative 9a ([(3S)-6-({2',6'-dimethyl-4'-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro- 1-benzofuran-3-yl]acetic acid hemi-hydrate, TAK-875) as a potent, selective, and orally bioavailable GPR40 agonist, with a pharmacokinetic profile enabling long-acting drug efficacy. Compound, 9a showed potent plasma glucose-lowering action and insulinotropic action during an oral glucose tolerance test in female Wistar fatty rats with impaired glucose tolerance. Compound 9a is currently in clinical trials for the treatment of type 2 diabetes mellitus.