2. Academic Validation
  3. 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)

  • J Med Chem. 2015 Jul 23;58(14):5579-98. doi: 10.1021/acs.jmedchem.5b00606.
Marianne Lucas-Hourani 1 2,  Hélène Munier-Lehmann 3 4,  Farah El Mazouni 5,  Nicholas A Malmquist 6 7 8,  Jane Harpon 6 7 8,  Eloi P Coutant 3 4,  Sandrine Guillou 3 4,  Olivier Helynck 3 4,  Anne Noel 3 4,  Artur Scherf 6 7 8,  Margaret A Phillips 5,  Frédéric Tangy 1 2,  Pierre-Olivier Vidalain 1 2,  Yves L Janin 3 4
Affiliations

Affiliations

  • 1 †Unité de Génomique Virale et Vaccination, Département de Virologie, Institut Pasteur, 28 Rue du Dr. Roux, 75724 Paris Cedex 15, France.
  • 2 ‡Unité Mixte de Recherche 3569, Centre National de la Recherche Scientifique, 25 Rue du Dr. Roux, 75724 Paris Cedex 15, France.
  • 3 §Unité Mixte de Recherche 3523, Centre National de la Recherche Scientifique, 28 Rue du Dr. Roux, 75724 Paris Cedex 15, France.
  • 4 ∥Unité de Chimie et Biocatalyse, Département de Biologie Structurale et Chimie, Institut Pasteur, 28 Rue du Dr. Roux, 75724 Paris Cedex 15, France.
  • 5 ⊥Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, 6001 Forest Park Boulevard, Dallas, Texas 75390-9041, United States.
  • 6 #Unité de Biologie des Interactions Hôte-Parasite, Département de Parasitologie et Mycologie, Institut Pasteur, 25 rue du Dr. Roux, 75724 Paris Cedex 15, France.
  • 7 ^Unité 1201, Institut National de la Santé et de la Recherche Médicale, 25 Rue du Dr. Roux, 75724 Paris Cedex 15, France.
  • 8 +Equipe de Recherche Labellisée 9195, Centre National de la Recherche Scientifique, 25 Rue du Dr. Roux, 75724 Paris Cedex 15, France.
PMID: 26079043 DOI: 10.1021/acs.jmedchem.5b00606
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.

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