Liu K, Xu L, Szalkowski D, Li Z, Ding V, Kwei G, Huskey S, Moller D E, Heck J V, Zhang B B, Jones A B
Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, USA.
J Med Chem. 2000 Sep 21;43(19):3487-94. doi: 10.1021/jm000285q.
A series of 3,6-diaryl-2,5-dihydroxybenzoquinones were synthesized and evaluated for their abilities to selectively activate human insulin receptor tyrosine kinase (IRTK). 2, 5-Dihydroxy-6-(1-methylindol-3-yl)-3-phenyl-1,4-benzoquinone (2h) was identified as a potent, highly selective, and orally active small-molecule insulin receptor activator. It activated IRTK with an EC(50) of 300 nM and did not induce the activation of closely related receptors (IGFIR, EGFR, and PDGFR) at concentrations up to 30 000 nM. Oral administration of the compound to hyperglycemic db/db mice (0.1-10 mg/kg/day) elicited substantial to nearly complete correction of hyperglycemia in a dose-dependent manner. In ob/ob mice, the compound (10 mg/kg) caused significant reduction in hyperinsulinemia. A structurally related compound 2c, inactive in IRTK assay, failed to affect blood glucose level in db/db mice at equivalent exposure levels. Results from additional studies with compound 2h, aimed at evaluating classical quinone-related phenomena, provided sufficient grounds for optimism to allow more extensive toxicologic evaluation.
合成了一系列3,6-二芳基-2,5-二羟基苯醌，并评估了它们选择性激活人胰岛素受体酪氨酸激酶（IRTK）的能力。2,5-二羟基-6-(1-甲基吲哚-3-基)-3-苯基-1,4-苯醌（2h）被鉴定为一种强效、高度选择性且口服活性的小分子胰岛素受体激活剂。它以300 nM的EC(50)激活IRTK，在浓度高达30000 nM时不会诱导密切相关受体（IGFIR、EGFR和PDGFR）的激活。给高血糖db/db小鼠口服该化合物（0.1-10 mg/kg/天），以剂量依赖的方式使高血糖得到显著至几乎完全的纠正。在ob/ob小鼠中，该化合物（10 mg/kg）使高胰岛素血症显著降低。一种在IRTK测定中无活性的结构相关化合物2c，在等效暴露水平下对db/db小鼠的血糖水平没有影响。对化合物2h进行的旨在评估经典醌相关现象的额外研究结果，为进行更广泛的毒理学评估提供了充分的乐观依据。
