A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria.
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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, Benito Francisco Javier Gamo, Alonso Laura Maria Sanz, Martinez Maria Santos, Jimenez-Diaz Maria Belen, Bazaga Santiago Ferrer, Angulo-Barturen Iñigo, 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
Аннотация
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.