title: Original 2-(3-alkoxy-1H-pyrazol-1-yl)pyrimidine derivatives as inhibitors of human dihydroorotate dehydrogenase (DHODH).
abstract: From a research program aimed at the design of new chemical entities followed by extensive screening on various models of infectious diseases, an original series of 2-(3-alkoxy-1H-pyrazol-1-yl)pyrimidines endowed with notable antiviral properties were found. Using a whole cell measles virus replication assay, we describe here some aspects of the iterative process that, from 2-(4-benzyl-3-ethoxy-5-methyl-1H-pyrazol-1-yl)pyrimidine, led to 2-(4-(2,6-difluorophenoxy)-3-isopropoxy-5-methyl-1H-pyrazol-1-yl)-5-ethylpyrimidine and a 4000-fold improvement of antiviral activity with a subnanomolar level of inhibition. Moreover, recent precedents in the literature describing antiviral derivatives acting at the level of the de novo pyrimidine biosynthetic pathway led us to determine that the mode of action of this series is based on the inhibition of the cellular dihydroorotate dehydrogenase (DHODH), the fourth enzyme of this pathway. Biochemical studies with recombinant human DHODH led us to measure IC50 as low as 13 nM for the best example of this original series when using 2,3-dimethoxy-5-methyl-6-(3-methyl-2-butenyl)-1,4-benzoquinone (coenzyme Q1) as a surrogate for coenzyme Q10, the cofactor of this enzyme.
authors.affiliation: Unité de Chimie et Biocatalyse, Département de Biologie Structurale et Chimie, Institut Pasteur , 28 Rue du Dr. Roux, 75724 Paris Cedex 15, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Munier-Lehmann
authors.forename: Marianne
authors.initials: M
authors.lastname: Lucas-Hourani
authors.forename: Sandrine
authors.initials: S
authors.lastname: Guillou
authors.forename: Olivier
authors.initials: O
authors.lastname: Helynck
authors.forename: Gigliola
authors.initials: G
authors.lastname: Zanghi
authors.forename: Anne
authors.initials: A
authors.lastname: Noel
authors.forename: Frédéric
authors.initials: F
authors.lastname: Tangy
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Vidalain
authors.forename: Yves L
authors.initials: YL
authors.lastname: Janin
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D044925:Oxidoreductases Acting on CH-CH Group Donors