title: 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.affiliation: 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.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Phillips
authors.affiliation: Medicines for Malaria Venture, 1215 Geneva, Switzerland.
authors.forename: Julie
authors.initials: J
authors.lastname: Lotharius
authors.affiliation: Abbvie, 1 North Waukegan Road, North Chicago, IL 60064-6104, USA.
authors.forename: Kennan
authors.initials: K
authors.lastname: Marsh
authors.affiliation: Departments of Chemistry and Global Health, University of Washington, Seattle, WA 98195, USA.
authors.forename: John
authors.initials: J
authors.lastname: White
authors.affiliation: Medicines for Malaria Venture, 1215 Geneva, Switzerland.
authors.forename: Anthony
authors.initials: A
authors.lastname: Dayan
authors.affiliation: Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
authors.forename: Karen L
authors.initials: KL
authors.lastname: White
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, 6001 Forest Park Boulevard, Dallas, TX 75390-9041, USA.
authors.forename: Jacqueline W
authors.initials: JW
authors.lastname: Njoroge
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, 6001 Forest Park Boulevard, Dallas, TX 75390-9041, USA.
authors.forename: Farah
authors.initials: F
authors.lastname: El Mazouni
authors.affiliation: Abbvie, 1 North Waukegan Road, North Chicago, IL 60064-6104, USA.
authors.forename: Yanbin
authors.initials: Y
authors.lastname: Lao
authors.affiliation: Departments of Chemistry and Global Health, University of Washington, Seattle, WA 98195, USA.
authors.forename: Sreekanth
authors.initials: S
authors.lastname: Kokkonda
authors.affiliation: Department of Biophysics, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390-9041, USA.
authors.forename: Diana R
authors.initials: DR
authors.lastname: Tomchick
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, 6001 Forest Park Boulevard, Dallas, TX 75390-9041, USA.
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Deng
authors.affiliation: Medicines for Malaria Venture, 1215 Geneva, Switzerland.
authors.forename: Trevor
authors.initials: T
authors.lastname: Laird
authors.affiliation: Health Sciences and Technology/Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Sangeeta N
authors.initials: SN
authors.lastname: Bhatia
authors.affiliation: Health Sciences and Technology/Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: March
authors.affiliation: Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Caroline L
authors.initials: CL
authors.lastname: Ng
authors.affiliation: 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.
authors.forename: David A
authors.initials: DA
authors.lastname: Fidock
authors.affiliation: Swiss Tropical and Public Health Institute, Socinstrasse 57, 4002 Basel, Switzerland. University of Basel, 4003 Basel, Switzerland.
authors.forename: Sergio
authors.initials: S
authors.lastname: Wittlin
authors.affiliation: GlaxoSmithKline (GSK), Tres Cantos Medicines Development Campus, Severo Ochoa, Madrid 28760, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Lafuente-Monasterio
authors.affiliation: GlaxoSmithKline (GSK), Tres Cantos Medicines Development Campus, Severo Ochoa, Madrid 28760, Spain.
authors.forename: Francisco Javier Gamo
authors.initials: FJ
authors.lastname: Benito
authors.affiliation: GlaxoSmithKline (GSK), Tres Cantos Medicines Development Campus, Severo Ochoa, Madrid 28760, Spain.
authors.forename: Laura Maria Sanz
authors.initials: LM
authors.lastname: Alonso
authors.affiliation: GlaxoSmithKline (GSK), Tres Cantos Medicines Development Campus, Severo Ochoa, Madrid 28760, Spain.
authors.forename: Maria Santos
authors.initials: MS
authors.lastname: Martinez
authors.affiliation: GlaxoSmithKline (GSK), Tres Cantos Medicines Development Campus, Severo Ochoa, Madrid 28760, Spain.
authors.forename: Maria Belen
authors.initials: MB
authors.lastname: Jimenez-Diaz
authors.affiliation: GlaxoSmithKline (GSK), Tres Cantos Medicines Development Campus, Severo Ochoa, Madrid 28760, Spain.
authors.forename: Santiago Ferrer
authors.initials: SF
authors.lastname: Bazaga
authors.affiliation: GlaxoSmithKline (GSK), Tres Cantos Medicines Development Campus, Severo Ochoa, Madrid 28760, Spain.
authors.forename: Iñigo
authors.initials: I
authors.lastname: Angulo-Barturen
authors.affiliation: GlaxoSmithKline (GSK), Tres Cantos Medicines Development Campus, Severo Ochoa, Madrid 28760, Spain.
authors.forename: John N
authors.initials: JN
authors.lastname: Haselden
authors.affiliation: GSK, Park Road, Ware, Hertfordshire SG12 0DP, UK.
authors.forename: James
authors.initials: J
authors.lastname: Louttit
authors.affiliation: GSK, Park Road, Ware, Hertfordshire SG12 0DP, UK.
authors.forename: Yi
authors.initials: Y
authors.lastname: Cui
authors.affiliation: GSK, Park Road, Ware, Hertfordshire SG12 0DP, UK.
authors.forename: Arun
authors.initials: A
authors.lastname: Sridhar
authors.affiliation: Biomedical Primate Research Centre, P.O. Box 3306, 2280 GH Rijswijk, Netherlands.
authors.forename: Anna-Marie
authors.initials: AM
authors.lastname: Zeeman
authors.affiliation: Biomedical Primate Research Centre, P.O. Box 3306, 2280 GH Rijswijk, Netherlands.
authors.forename: Clemens
authors.initials: C
authors.lastname: Kocken
authors.affiliation: TropIQ Health Sciences, 6525 GA Nijmegen, Netherlands.
authors.forename: Robert
authors.initials: R
authors.lastname: Sauerwein
authors.affiliation: TropIQ Health Sciences, 6525 GA Nijmegen, Netherlands.
authors.forename: Koen
authors.initials: K
authors.lastname: Dechering
authors.affiliation: Discovery Biology, Eskitis Institute for Drug Discovery, Griffith University, Nathan, Queensland 4111, Australia.
authors.forename: Vicky M
authors.initials: VM
authors.lastname: Avery
authors.affiliation: Discovery Biology, Eskitis Institute for Drug Discovery, Griffith University, Nathan, Queensland 4111, Australia.
authors.forename: Sandra
authors.initials: S
authors.lastname: Duffy
authors.affiliation: Imperial College of Science Technology and Medicine, London SW7 2AY, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Delves
authors.affiliation: Imperial College of Science Technology and Medicine, London SW7 2AY, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Sinden
authors.affiliation: Imperial College of Science Technology and Medicine, London SW7 2AY, UK.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ruecker
authors.affiliation: State University of New York Upstate Medical University, Syracuse, NY 13210, USA.
authors.forename: Kristina S
authors.initials: KS
authors.lastname: Wickham
authors.affiliation: State University of New York Upstate Medical University, Syracuse, NY 13210, USA.
authors.forename: Rosemary
authors.initials: R
authors.lastname: Rochford
authors.affiliation: SRI International, Menlo Park, CA 94025, USA.
authors.forename: Janet
authors.initials: J
authors.lastname: Gahagen
authors.affiliation: SRI International, Menlo Park, CA 94025, USA.
authors.forename: Lalitha
authors.initials: L
authors.lastname: Iyer
authors.affiliation: SRI International, Menlo Park, CA 94025, USA.
authors.forename: Ed
authors.initials: E
authors.lastname: Riccio
authors.affiliation: SRI International, Menlo Park, CA 94025, USA.
authors.forename: Jon
authors.initials: J
authors.lastname: Mirsalis
authors.affiliation: Medicines for Malaria Venture, 1215 Geneva, Switzerland.
authors.forename: Ian
authors.initials: I
authors.lastname: Bathhurst
authors.affiliation: Medicines for Malaria Venture, 1215 Geneva, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rueckle
authors.affiliation: Medicines for Malaria Venture, 1215 Geneva, Switzerland.
authors.forename: Xavier
authors.initials: X
authors.lastname: Ding
authors.affiliation: Medicines for Malaria Venture, 1215 Geneva, Switzerland.
authors.forename: Brice
authors.initials: B
authors.lastname: Campo
authors.affiliation: Medicines for Malaria Venture, 1215 Geneva, Switzerland.
authors.forename: Didier
authors.initials: D
authors.lastname: Leroy
authors.affiliation: National Institutes for Allergy and Infectious Diseases, 6610 Rockledge Drive, Bethesda, MD 20892, USA.
authors.forename: M John
authors.initials: MJ
authors.lastname: Rogers
authors.affiliation: Departments of Chemistry and Global Health, University of Washington, Seattle, WA 98195, USA.
authors.forename: Pradipsinh K
authors.initials: PK
authors.lastname: Rathod
authors.affiliation: Medicines for Malaria Venture, 1215 Geneva, Switzerland.
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Burrows
authors.affiliation: Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia. margaret.phillips@utsouthwestern.edu susan.charman@monash.edu.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Charman
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000493:pharmacokinetics; D019540:Area Under Curve; D018938:Caco-2 Cells; D018360:Crystallography, X-Ray; D000090722:Dihydroorotate Dehydrogenase; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics; D000882:Haplorhini; D006801:Humans; D020128:Inhibitory Concentration 50; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000517:prevention & control*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008969:Molecular Sequence Data; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors* / Q000737:chemistry; D010963:Plasmodium falciparum; D011743:Pyrimidines / Q000737:chemistry* / Q000493:pharmacokinetics; D011817:Rabbits; D013379:Substrate Specificity; D014230:Triazoles / Q000737:chemistry* / Q000493:pharmacokinetics
chemical_list: D000962:Antimalarials; D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D014230:Triazoles; C000606979:DSM265; D044925:Oxidoreductases Acting on CH-CH Group Donors