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Sci Transl Med. 2015 Jul 15;7(296):296ra111. doi: 10.1126/scitranslmed.aaa6645.

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

Author information

1
Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, 6001 Forest Park Boulevard, Dallas, TX 75390-9041, USA. margaret.phillips@utsouthwestern.edu susan.charman@monash.edu.
2
Medicines for Malaria Venture, 1215 Geneva, Switzerland.
3
Abbvie, 1 North Waukegan Road, North Chicago, IL 60064-6104, USA.
4
Departments of Chemistry and Global Health, University of Washington, Seattle, WA 98195, USA.
5
Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
6
Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, 6001 Forest Park Boulevard, Dallas, TX 75390-9041, USA.
7
Department of Biophysics, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-9041, USA.
8
Health Sciences and Technology/Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
9
Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA.
10
Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA. Division of Infectious Diseases, Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA.
11
Swiss Tropical and Public Health Institute, Socinstrasse 57, 4002 Basel, Switzerland. University of Basel, 4003 Basel, Switzerland.
12
GlaxoSmithKline (GSK), Tres Cantos Medicines Development Campus, Severo Ochoa, Madrid 28760, Spain.
13
GSK, Park Road, Ware, Hertfordshire SG12 0DP, UK.
14
Biomedical Primate Research Centre, P.O. Box 3306, 2280 GH Rijswijk, Netherlands.
15
TropIQ Health Sciences, 6525 GA Nijmegen, Netherlands.
16
Discovery Biology, Eskitis Institute for Drug Discovery, Griffith University, Nathan, Queensland 4111, Australia.
17
Imperial College of Science Technology and Medicine, London SW7 2AY, UK.
18
State University of New York Upstate Medical University, Syracuse, NY 13210, USA.
19
SRI International, Menlo Park, CA 94025, USA.
20
National Institutes for Allergy and Infectious Diseases, 6610 Rockledge Drive, Bethesda, MD 20892, USA.
21
Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia. margaret.phillips@utsouthwestern.edu susan.charman@monash.edu.

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.

PMID:
26180101
PMCID:
PMC4539048
DOI:
10.1126/scitranslmed.aaa6645
[Indexed for MEDLINE]
Free PMC Article

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