Original 2-(3-Alkoxy-1H-pyrazol-1-yl)azines Inhibitors of Human Dihydroorotate Dehydrogenase (DHODH).
Original 2-(3-Alkoxy-1H-pyrazol-1-yl)azines Inhibitors of Human Dihydroorotate Dehydrogenase (DHODH).
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DOI：
10.1021/acs.jmedchem.5b00606
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发表时间：
2015-07-23
影响因子：
7.3
通讯作者：
Janin YL
中科院分区：
文献类型：
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作者：
Lucas-Hourani M;Munier-Lehmann H;El Mazouni F;Malmquist NA;Harpon J;Coutant EP;Guillou S;Helynck O;Noel A;Scherf A;Phillips MA;Tangy F;Vidalain PO;Janin YL
在我们发现2-（3-烷氧基-1H-吡唑-1-基）嘧啶衍生物以及2-（4-苄基-3-乙氧基-5-甲基-1H-吡唑-1-基）-5-甲基吡啶对人二氢乳清酸脱氢酶（DHODH）的抑制作用后，我们在此描述了一系列含吖嗪类似物的合成和评价。与我们之前的报告一样，这一系列人DHODH抑制剂的结构-活性研究是基于测量麻疹病毒复制的表型测定。在其他抑制剂中，这一轮的合成和生物评价迭代导致了高活性的5-环丙基-2-（4-（2，6-二氟苯氧基）-3-异丙氧基-5-甲基-1H-吡唑-1-基）-3-氟吡啶。在一系列体外试验中证实了该化合物对DHODH的抑制作用，包括用于病毒复制和细胞生长的酶试验和基于细胞的试验。发现该分子比已知的DHODH、布喹那和特立氟胺的抑制剂更有活性，从而为其用作工具或设计原始系列免疫抑制剂开辟了前景。此外，因为已经发现其它系列的人DHODH抑制剂也影响恶性疟原虫DHODH，所以测定所有化合物对恶性疟原虫生长的影响。然而，仅在两种化合物中观察到的适度体外抑制作用与其对恶性疟原虫DHODH的抑制作用无关。
Following our discovery of human dihydroorotate dehydrogenase (DHODH) inhibition by 2-(3-alkoxy-1H-pyrazol-1-yl)pyrimidine derivatives as well as 2-(4-benzyl-3-ethoxy-5-methyl-1H-pyrazol-1-yl)-5-methylpyridine, we describe here the syntheses and evaluation of an array of azine-bearing analogues. As in our previous report, the structure–activity study of this series of human DHODH inhibitors was based on a phenotypic assay measuring measles virus replication. Among other inhibitors, this round of syntheses and biological evaluation iteration led to the highly active 5-cyclopropyl-2-(4-(2,6-difluorophenoxy)-3-isopropoxy-5-methyl-1H-pyrazol-1-yl)-3-fluoropyridine. Inhibition of DHODH by this compound was confirmed in an array of in vitro assays, including enzymatic tests and cell-based assays for viral replication and cellular growth. This molecule was found to be more active than the known inhibitors of DHODH, brequinar and teriflunomide, thus opening perspectives for its use as a tool or for the design of an original series of immunosuppressive agent. Moreover, because other series of inhibitors of human DHODH have been found to also affect Plasmodium falciparum DHODH, all the compounds were assayed for their effect on P. falciparum growth. However, the modest in vitro inhibition solely observed for two compounds did not correlate with their inhibition of P. falciparum DHODH.