Human dihydroorotate dehydrogenase (hDHODH) catalyzes the rate-limiting step in de novo pyrimidine biosynthesis, the conversion of dihydroorotate to orotate. hDHODH has recently been found to be associated with acute myelogenous leukemia, a disease for which the standard of intensive care has not changed over decades. This work presents a novel class of hDHODH inhibitors, which are based on an unusual carboxylic group bioisostere 2-hydroxypyrazolo[1,5-a]pyridine, that has been designed starting from brequinar, one of the most potent hDHODH inhibitors. A combination of structure-based and ligand-based strategies produced compound 4, which shows brequinar-like hDHODH potency in vitro and is superior in terms of cytotoxicity and immunosuppression. Compound 4 also restores myeloid differentiation in leukemia cell lines at concentrations that are one log digit lower than those achieved in experiments with brequinar. This Article reports the design, synthesis, SAR, X-ray crystallography, biological assays, and physicochemical characterization of the new class of hDHODH inhibitors.

中文翻译：

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使用有效的2-羟基吡唑并[1,5- a ]吡啶骨架的人二氢乳清酸酯脱氢酶抑制剂靶向骨髓分化

人二氢乳清酸酯脱氢酶（h DHODH）催化从头进行嘧啶生物合成的速率限制步骤，即二氢乳清酸酯转化为乳清酸酯。h最近发现DHODH与急性骨髓性白血病有关，这种疾病的重症监护标准在几十年内没有改变。这项工作提出了一种新型的h DHODH抑制剂，它基于一种不寻常的羧基生物甾体2-羟基吡唑并[1,5- a ]吡啶，该化合物是从最有效的h DHODH抑制剂之一布雷喹纳开始设计的。基于结构的策略和基于配体的策略的组合产生了化合物4，该化合物显示出类似布雷奎纳尔的hDHODH在体外的效力很高，在细胞毒性和免疫抑制方面也很出色。化合物4还以比使用布雷奎纳的实验所获得的浓度低一个对数位的浓度恢复白血病细胞系中的髓样分化。本文报道了新型h DHODH抑制剂的设计，合成，SAR，X射线晶体学，生物学分析和理化特性。