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

Marianne Lucas-Hourani, Hélène Munier-Lehmann, Farah El Mazouni, Nicholas A. Malmquist, Jane Harpon, Eloi P. Coutant, Sandrine Guillou, Olivier Helynck, Anne Noel, Artur Scherf, Margaret A. Phillips, Frédéric Tangy, Pierre Olivier Vidalain, Yves L. Janin

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5579-5598
Number of pages20
JournalJournal of Medicinal Chemistry
Volume58
Issue number14
DOIs
StatePublished - Jul 23 2015

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Plasmodium falciparum
brequinar
Measles virus
Enzyme Assays
Immunosuppressive Agents
Virus Replication
Growth
dihydroorotate dehydrogenase
alkoxyl radical
In Vitro Techniques

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Lucas-Hourani, M., Munier-Lehmann, H., El Mazouni, F., Malmquist, N. A., Harpon, J., Coutant, E. P., ... Janin, Y. L. (2015). Original 2-(3-Alkoxy-1 H -pyrazol-1-yl)azines Inhibitors of Human Dihydroorotate Dehydrogenase (DHODH). Journal of Medicinal Chemistry, 58(14), 5579-5598. https://doi.org/10.1021/acs.jmedchem.5b00606

Original 2-(3-Alkoxy-1 H -pyrazol-1-yl)azines Inhibitors of Human Dihydroorotate Dehydrogenase (DHODH). / Lucas-Hourani, Marianne; Munier-Lehmann, Hélène; El Mazouni, Farah; Malmquist, Nicholas A.; Harpon, Jane; Coutant, Eloi P.; Guillou, Sandrine; Helynck, Olivier; Noel, Anne; Scherf, Artur; Phillips, Margaret A.; Tangy, Frédéric; Vidalain, Pierre Olivier; Janin, Yves L.

In: Journal of Medicinal Chemistry, Vol. 58, No. 14, 23.07.2015, p. 5579-5598.

Research output: Contribution to journalArticle

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 2015, 'Original 2-(3-Alkoxy-1 H -pyrazol-1-yl)azines Inhibitors of Human Dihydroorotate Dehydrogenase (DHODH)', Journal of Medicinal Chemistry, vol. 58, no. 14, pp. 5579-5598. https://doi.org/10.1021/acs.jmedchem.5b00606
Lucas-Hourani M, Munier-Lehmann H, El Mazouni F, Malmquist NA, Harpon J, Coutant EP et al. Original 2-(3-Alkoxy-1 H -pyrazol-1-yl)azines Inhibitors of Human Dihydroorotate Dehydrogenase (DHODH). Journal of Medicinal Chemistry. 2015 Jul 23;58(14):5579-5598. https://doi.org/10.1021/acs.jmedchem.5b00606
Lucas-Hourani, Marianne ; Munier-Lehmann, Hélène ; El Mazouni, Farah ; Malmquist, Nicholas A. ; Harpon, Jane ; Coutant, Eloi P. ; Guillou, Sandrine ; Helynck, Olivier ; Noel, Anne ; Scherf, Artur ; Phillips, Margaret A. ; Tangy, Frédéric ; Vidalain, Pierre Olivier ; Janin, Yves L. / Original 2-(3-Alkoxy-1 H -pyrazol-1-yl)azines Inhibitors of Human Dihydroorotate Dehydrogenase (DHODH). In: Journal of Medicinal Chemistry. 2015 ; Vol. 58, No. 14. pp. 5579-5598.
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AU - Coutant, Eloi P.

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AU - Noel, Anne

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