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

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 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.

• Authors: 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 Benito, Laura 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
• Journal: Science translational medicine (Sci Transl Med) Vol. 7 Issue 296 Pg. 296ra111 (Jul 15 2015) ISSN: 1946-6242 [Electronic] United States
• PMID: 26180101 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015, American Association for the Advancement of Science.

Chemical References

• Antimalarials
• Dihydroorotate Dehydrogenase
• Enzyme Inhibitors
• Pyrimidines
• Triazoles
• DSM265
• Oxidoreductases Acting on CH-CH Group Donors

Topics

• Administration, Oral
• Animals
• Antimalarials (chemistry, pharmacokinetics)
• Area Under Curve
• Caco-2 Cells
• Crystallography, X-Ray
• Dihydroorotate Dehydrogenase
• Dogs
• Drug Evaluation, Preclinical
• Enzyme Inhibitors (chemistry, pharmacokinetics)
• Haplorhini
• Humans
• Inhibitory Concentration 50
• Malaria, Falciparum (drug therapy, prevention & control)
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Molecular Sequence Data
• Oxidoreductases Acting on CH-CH Group Donors (antagonists & inhibitors, chemistry)
• Plasmodium falciparum
• Pyrimidines (chemistry, pharmacokinetics)
• Rabbits
• Substrate Specificity
• Triazoles (chemistry, pharmacokinetics)