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  • A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria

    Author(s)
    Phillips, Margaret A
    Lotharius, Julie
    Marsh, Kennan
    White, John
    Dayan, Anthony
    White, Karen L
    Njoroge, Jacqueline W
    El Mazouni, Farah
    Lao, Yanbin
    Kokkonda, Sreekanth
    Tomchick, Diana R
    Deng, Xiaoyi
    Laird, Trevor
    Bhatia, Sangeeta N
    March, Sandra
    Ng, Caroline L
    Fidock, David A
    Wittlin, Sergio
    Lafuente-Monasterio, Maria
    Gamo Benito, Francisco Javier
    Sanz Alonso, Laura Maria
    Santos Martinez, Maria
    Belen Jimenez-Diaz, Maria
    Ferrer Bazaga, Santiago
    Angulo-Barturen, Inigo
    Haselden, John N
    Louttit, James
    Cui, Yi
    Sridhar, Arun
    Zeeman, Anna-Marie
    Kocken, Clemens
    Sauerwein, Robert
    Dechering, Koen
    Avery, Vicky M
    Duffy, Sandra
    Delves, Michael
    Sinden, Robert
    Ruecker, Andrea
    Wickham, Kristina S
    Rochford, Rosemary
    Gahagen, Janet
    Iyer, Lalitha
    Riccio, Ed
    Mirsalis, Jon
    Bathhurst, Ian
    Rueckle, Thomas
    Ding, Xavier
    Campo, Brice
    Leroy, Didier
    Rogers, M John
    Rathod, Pradipsinh K
    Burrows, Jeremy N
    Charman, Susan A
    Griffith University Author(s)
    Duffy, Sandra
    Avery, Vicky M.
    Year published
    2015
    Metadata
    Show full item record
    Abstract
    Malaria is one of the most significant causes of childhood mortality, but disease control efforts are threatened by resistance of the Plasmodium parasite to current therapies. Continued progress in combating malaria requires development of new, easy to administer drug combinations with broad-ranging activity against all manifestations of the disease. DSM265, a triazolopyrimidine-based inhibitor of the pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH), is the first DHODH inhibitor to reach clinical development for treatment of malaria. We describe studies profiling the biological activity, pharmacological ...
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    Malaria is one of the most significant causes of childhood mortality, but disease control efforts are threatened by resistance of the Plasmodium parasite to current therapies. Continued progress in combating malaria requires development of new, easy to administer drug combinations with broad-ranging activity against all manifestations of the disease. DSM265, a triazolopyrimidine-based inhibitor of the pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH), is the first DHODH inhibitor to reach clinical development for treatment of malaria. We describe studies profiling the biological activity, pharmacological and pharmacokinetic properties, and safety of DSM265, which supported its advancement to human trials. DSM265 is highly selective toward DHODH of the malaria parasite Plasmodium, efficacious against both blood and liver stages of P. falciparum, and active against drug-resistant parasite isolates. Favorable pharmacokinetic properties of DSM265 are predicted to provide therapeutic concentrations for more than 8 days after a single oral dose in the range of 200 to 400 mg. DSM265 was well tolerated in repeat-dose and cardiovascular safety studies in mice and dogs, was not mutagenic, and was inactive against panels of human enzymes/receptors. The excellent safety profile, blood- and liver-stage activity, and predicted long half-life in humans position DSM265 as a new potential drug combination partner for either single-dose treatment or once-weekly chemoprevention. DSM265 has advantages over current treatment options that are dosed daily or are inactive against the parasite liver stage.
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    Journal Title
    Science Translational Medicine
    Volume
    7
    Issue
    296
    DOI
    https://doi.org/10.1126/scitranslmed.aaa6645
    Subject
    Medicinal and biomolecular chemistry not elsewhere classified
    Biological sciences
    Biomedical and clinical sciences
    Publication URI
    http://hdl.handle.net/10072/125290
    Collection
    • Journal articles

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