Original 2-(3-Alkoxy-1H-pyrazol-1-yl)azines Inhibitors of Human Dihydroorotate Dehydrogenase (DHODH)

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• 作者：Marianne Lucas-Hourani ; H茅l猫ne Munier-Lehmann ; Farah El Mazouni ; Nicholas A. Malmquist ; Jane Harpon ; Eloi P. Coutant ; Sandrine Guillou ; Olivier Helynck ; Anne Noel ; Artur Scherf ; Margaret A. Phillips ; Fr茅d茅ric Tangy ; Pierre-Olivier Vidalain ; Yves L. Janin
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：July 23, 2015
• 年：2015
• 卷：58
• 期：14
• 页码：5579-5598
• 全文大小：641K
• ISSN：1520-4804

文摘

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鈥揳ctivity 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.