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首页> 外文期刊>Bioorganic and Medicinal Chemistry Letters >The discovery of the benzhydroxamate MEK inhibitors CI-1040 and PD 0325901.
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The discovery of the benzhydroxamate MEK inhibitors CI-1040 and PD 0325901.

机译：苯氧肟酸酯MEK抑制剂CI-1040和PD 0325901的发现。

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摘要

A novel series of benzhydroxamate esters derived from their precursor anthranilic acids have been prepared and have been identified as potent MEK inhibitors. 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-benzamide, CI-1040, was the first MEK inhibitor to demonstrate in vivo activity in preclinical animal models and subsequently became the first MEK inhibitor to enter clinical trial. CI-1040 suffered however from poor exposure due to its poor solubility and rapid clearance, and as a result, development of the compound was terminated. Optimization of the diphenylamine core and modification of the hydroxamate side chain for cell potency, solubility, and exposure with oral delivery resulted in the discovery of the clinical candidate N-(2,3-dihydroxy-propoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide PD 0325901.
机译：已经制备了衍生自其前体邻氨基苯甲酸的一系列新的苯氧异羟肟酸酯，并且已将其鉴定为有效的MEK抑制剂。 2-（2-氯-4-碘-苯基氨基）-N-环丙基甲氧基-3,4-二氟苯甲酰胺CI-1040是首个在临床前动物模型中表现出体内活性的MEK抑制剂，随后成为首个MEK抑制剂进入临床试验。但是，由于CI-1040的溶解性差，清除速度快，因此接触不良，结果终止了该化合物的显影。优化二苯胺核心和修饰异羟肟酸酯侧链以提高细胞效能，溶解性和口服给药的暴露性，从而发现了临床候选药物N-（2,3-二羟基-丙氧基）-3,4-二氟-2 -（2-氟-4-碘-苯基氨基）-苯甲酰胺PD 0325901。

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