34171-37-4Relevant articles and documents
Original 2-(3-alkoxy-1 H -pyrazol-1-yl)pyrimidine derivatives as inhibitors of human dihydroorotate dehydrogenase (DHODH)
Munier-Lehmann, Hélène,Lucas-Hourani, Marianne,Guillou, Sandrine,Helynck, Olivier,Zanghi, Gigliola,Noel, Anne,Tangy, Frédéric,Vidalain, Pierre-Olivier,Janin, Yves L.
, p. 860 - 877 (2015/01/30)
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.
Synthesis and structure-activity relationships of a novel series of pyrimidines as potent inhibitors of TBK1/IKKε kinases
McIver, Edward G.,Bryans, Justin,Birchall, Kristian,Chugh, Jasveen,Drake, Thomas,Lewis, Stephen J.,Osborne, Joanne,Smiljanic-Hurley, Ela,Tsang, William,Kamal, Ahmad,Levy, Alison,Newman, Michelle,Taylor, Debra,Arthur, J. Simon C.,Clark, Kristopher,Cohen, Philip
, p. 7169 - 7173,5 (2012/12/12)
The design, synthesis and structure-activity relationships of a novel series of 2,4-diamino-5-cyclopropyl pyrimidines is described. Starting from BX795, originally reported to be a potent inhibitor of PDK1, we have developed compounds with improved selectivity and drug-like properties. These compounds have been evaluated in a range of cellular and in vivo assays, enabling us to probe the putative role of the TBK1/IKKε pathway in inflammatory diseases.
H2-antihistaminics, XVIII: 5,6-alkyl-4-pyrimidones with H2-antihistaminic activity
Spengler,Schunack
, p. 425 - 430 (2007/10/02)
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