Discovery of a potent, highly selective, and orally efficacious small-molecule activator of the insulin receptor
Discovery of a potent, highly selective, and orally efficacious small-molecule activator of the insulin receptor
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DOI：
10.1021/jm000285q
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发表时间：
2000-09-21
影响因子：
7.3
通讯作者：
Jones, AB
中科院分区：
文献类型：
--
作者：
Liu, K;Xu, LB;Jones, AB
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) 被鉴定为一种有效的、高选择性的、口服活性的小分子胰岛素受体激活剂。它以 300 nM 的 EC50 激活 IRTK，并且在浓度高达 30 000 nM 时不会诱导密切相关受体（IGFIR、EGFR 和 PDGFR）的激活。向高血糖db/db小鼠口服该化合物（0.1-10mg/kg/天）以剂量依赖性方式引起基本上至几乎完全的高血糖纠正。在 ob/ob 小鼠中，该化合物（10 mg/kg）显着降低了高胰岛素血症。结构相关的化合物 2c 在 IRTK 测定中无活性，在同等暴露水平下未能影响 db/db 小鼠的血糖水平。旨在评估经典醌相关现象的化合物 2h 的其他研究结果为进行更广泛的毒理学评估提供了足够的乐观理由。
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 EC50 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.