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

Margaret A. Phillips, Julie Lotharius, Kennan Marsh, John White, Anthony Dayan, Karen L. White, Jacqueline W. Njoroge, Farah El Mazouni, Yanbin Lao, Sreekanth Kokkonda, Diana R. Tomchick, Xiaoyi Deng, Trevor Laird, Sangeeta N. Bhatia, Sandra March, Caroline L. Ng, David A. Fidock, Sergio Wittlin, Maria Lafuente-Monasterio, Francisco Javier Gamo BenitoLaura Maria Sanz Alonso, Maria Santos Martinez, Maria Belen Jimenez-Diaz, Santiago Ferrer Bazaga, Iñigo Angulo-Barturen, John N. Haselden, James Louttit, Yi Cui, Arun Sridhar, Anna Marie Zeeman, Clemens Kocken, Robert Sauerwein, Koen Dechering, Vicky M. Avery, Sandra Duffy, Michael Delves, Robert Sinden, Andrea Ruecker, Kristina S. Wickham, Rosemary Rochford, Janet Gahagen, Lalitha Iyer, Ed Riccio, Jon Mirsalis, Ian Bathhurst, Thomas Rueckle, Xavier Ding, Brice Campo, Didier Leroy, M. John Rogers, Pradipsinh K. Rathod, Jeremy N. Burrows, Susan A. Charman

Research output: Contribution to journalArticle

127 Scopus citations

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 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 drugresistant 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.

Original languageEnglish (US)
Article numberaaa6645
JournalScience translational medicine
Volume7
Issue number296
DOIs
StatePublished - Jul 15 2015
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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    Phillips, M. A., Lotharius, J., Marsh, K., White, J., Dayan, A., White, K. L., Njoroge, J. W., El Mazouni, F., Lao, Y., Kokkonda, S., Tomchick, D. R., Deng, X., Laird, T., Bhatia, S. N., March, S., Ng, C. L., Fidock, D. A., Wittlin, S., Lafuente-Monasterio, M., ... Charman, S. A. (2015). A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria. Science translational medicine, 7(296), [aaa6645]. https://doi.org/10.1126/scitranslmed.aaa6645