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

Autor: Rosemary Rochford, Kristina S. Wickham, Xavier C. Ding, David A. Fidock, Margaret A. Phillips, Thomas Rueckle, Sandra March, Brice Campo, Anna Marie Zeeman, Andrea Ruecker, Iñigo Angulo-Barturen, Xiaoyi Deng, Sergio Wittlin, Michael J. Delves, Farah El Mazouni, Susan A. Charman, Diana R. Tomchick, Laura Maria Sanz Alonso, Jacqueline W. Njoroge, Robert E. Sinden, Jeremy N. Burrows, Ian Bathhurst, Anthony Dayan, Lalitha V. Iyer, Trevor Laird, Koen J. Dechering, Caroline L. Ng, Sandra Duffy, Janet Gahagen, Jon C. Mirsalis, M. John Rogers, Kennan C. Marsh, Yanbin Lao, Pradipsinh K. Rathod, James B. Louttit, Santiago Ferrer Bazaga, Julie Lotharius, Yi Cui, Sreekanth Kokkonda, Francisco Javier Gamo Benito, Arun Sridhar, John H. White, María Santos Martínez, Maria J. Lafuente-Monasterio, María Belén Jiménez-Díaz, John N. Haselden, Sangeeta N. Bhatia, Didier Leroy, Robert W. Sauerwein, Clemens H. M. Kocken, Vicky M. Avery, Ed Riccio, Karen L. White
Přispěvatelé: Institute for Medical Engineering and Science, Harvard University--MIT Division of Health Sciences and Technology, Bhatia, Sangeeta N, March-Riera, Sandra
Rok vydání: 2015
Předmět:
Drug
Oxidoreductases Acting on CH-CH Group Donors
media_common.quotation_subject
Molecular Sequence Data
Plasmodium falciparum
Dihydroorotate Dehydrogenase
Drug Evaluation
Preclinical
lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4]
Administration
Oral
Mice
SCID
Pharmacology
Crystallography
X-Ray
Article
Substrate Specificity
Antimalarials
Inhibitory Concentration 50
Mice
03 medical and health sciences
Dogs
Pharmacokinetics
Mice
Inbred NOD
medicine
Animals
Humans
Enzyme Inhibitors
Malaria
Falciparum
030304 developmental biology
Dihydroorotate Dehydrogenase Inhibitor
media_common
0303 health sciences
biology
030306 microbiology
Biological activity
Haplorhini
General Medicine
Triazoles
Oxidoreductase inhibitor
medicine.disease
biology.organism_classification
3. Good health
Pyrimidines
Area Under Curve
Dihydroorotate dehydrogenase
Rabbits
Caco-2 Cells
Malaria
Zdroj: Science Translational Medicine, 7, 296, pp. 296ra111
Repositorio Institucional de la Consejería de Sanidad de la Comunidad de Madrid
Consejería de Sanidad de la Comunidad de Madrid
PMC
Science Translational Medicine, 7, 296ra111
ISSN: 1946-6242
1946-6234
Popis: 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.
Databáze: OpenAIRE
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