title: A Triazolopyrimidine-Based Dihydroorotate Dehydrogenase Inhibitor with Improved Drug-like Properties for Treatment and Prevention of Malaria.
abstract: The emergence of drug-resistant malaria parasites continues to hamper efforts to control this lethal disease. Dihydroorotate dehydrogenase has recently been validated as a new target for the treatment of malaria, and a selective inhibitor (DSM265) of the Plasmodium enzyme is currently in clinical development. With the goal of identifying a backup compound to DSM265, we explored replacement of the SF5-aniline moiety of DSM265 with a series of CF3-pyridinyls while maintaining the core triazolopyrimidine scaffold. This effort led to the identification of DSM421, which has improved solubility, lower intrinsic clearance, and increased plasma exposure after oral dosing compared to DSM265, while maintaining a long predicted human half-life. Its improved physical and chemical properties will allow it to be formulated more readily than DSM265. DSM421 showed excellent efficacy in the SCID mouse model of P. falciparum malaria that supports the prediction of a low human dose (<200 mg). Importantly DSM421 showed equal activity against both P. falciparum and P. vivax field isolates, while DSM265 was more active on P. falciparum. DSM421 has the potential to be developed as a single-dose cure or once-weekly chemopreventative for both P. falciparum and P. vivax malaria, leading to its advancement as a preclinical development candidate.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Phillips
authors.affiliation: Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, VIC 3052, Australia.
authors.forename: Karen L
authors.initials: KL
authors.lastname: White
authors.affiliation: Departments of Chemistry and Global Health, University of Washington , Seattle, Washington 98195, United States.
authors.forename: Sreekanth
authors.initials: S
authors.lastname: Kokkonda
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Deng
authors.affiliation: Departments of Chemistry and Global Health, University of Washington , Seattle, Washington 98195, United States.
authors.forename: John
authors.initials: J
authors.lastname: White
authors.forename: Farah
authors.initials: F
authors.lastname: El Mazouni
authors.affiliation: AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064-6104, United States.
authors.forename: Kennan
authors.initials: K
authors.lastname: Marsh
authors.forename: Diana R
authors.initials: DR
authors.lastname: Tomchick
authors.affiliation: Syngene International Ltd. , 560 099 Bangalore, India.
authors.forename: Krishne
authors.initials: K
authors.lastname: Manjalanagara
authors.affiliation: Syngene International Ltd. , 560 099 Bangalore, India.
authors.forename: Kakali Rani
authors.initials: KR
authors.lastname: Rudra
authors.affiliation: Global and Tropical Health Division, Menzies School of Health Research, Charles Darwin University , P.O. Box 41096, Casuarina, NT 0811, Australia.
authors.forename: Grennady
authors.initials: G
authors.lastname: Wirjanata
authors.affiliation: Eijkman Institute for Molecular Biology , Jl. Diponegoro 69, 10430 Jakarta, Indonesia.
authors.forename: Rintis
authors.initials: R
authors.lastname: Noviyanti
authors.affiliation: Global and Tropical Health Division, Menzies School of Health Research, Charles Darwin University , P.O. Box 41096, Casuarina, NT 0811, Australia.|Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford , Oxford OX3 7LJ, U.K.
authors.forename: Ric N
authors.initials: RN
authors.lastname: Price
authors.affiliation: Global and Tropical Health Division, Menzies School of Health Research, Charles Darwin University , P.O. Box 41096, Casuarina, NT 0811, Australia.
authors.forename: Jutta
authors.initials: J
authors.lastname: Marfurt
authors.affiliation: Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, VIC 3052, Australia.
authors.forename: David M
authors.initials: DM
authors.lastname: Shackleford
authors.affiliation: Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, VIC 3052, Australia.
authors.forename: Francis C K
authors.initials: FC
authors.lastname: Chiu
authors.affiliation: Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, VIC 3052, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Campbell
authors.affiliation: GlaxoSmithKline , Tres Cantos Medicines Development Campus, Severo Ochoa, Madrid 28760, Spain.
authors.forename: Maria Belen
authors.initials: MB
authors.lastname: Jimenez-Diaz
authors.affiliation: GlaxoSmithKline , Tres Cantos Medicines Development Campus, Severo Ochoa, Madrid 28760, Spain.
authors.forename: Santiago Ferrer
authors.initials: SF
authors.lastname: Bazaga
authors.affiliation: GlaxoSmithKline , Tres Cantos Medicines Development Campus, Severo Ochoa, Madrid 28760, Spain.
authors.forename: Iñigo
authors.initials: I
authors.lastname: Angulo-Barturen
authors.affiliation: GlaxoSmithKline , Tres Cantos Medicines Development Campus, Severo Ochoa, Madrid 28760, Spain.
authors.forename: Maria Santos
authors.initials: MS
authors.lastname: Martinez
authors.affiliation: GlaxoSmithKline , Tres Cantos Medicines Development Campus, Severo Ochoa, Madrid 28760, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Lafuente-Monasterio
authors.affiliation: Departments of Chemistry and Global Health, University of Washington , Seattle, Washington 98195, United States.
authors.forename: Werner
authors.initials: W
authors.lastname: Kaminsky
authors.affiliation: Centre Suisse de Recherches Scientifiques en Côte d'Ivoire , Km17, Route de Dabou, Adiopodoumé, BP 1303 Abidjan, Ivory Coast.
authors.forename: Kigbafori
authors.initials: K
authors.lastname: Silue
authors.affiliation: Biomedical Primate Research Centre , 2288 GJ Rijswijk, The Netherlands.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Zeeman
authors.affiliation: Biomedical Primate Research Centre , 2288 GJ Rijswijk, The Netherlands.
authors.forename: Clemens
authors.initials: C
authors.lastname: Kocken
authors.affiliation: Medicines for Malaria Venture , 1215 Geneva, Switzerland.
authors.forename: Didier
authors.initials: D
authors.lastname: Leroy
authors.affiliation: Medicines for Malaria Venture , 1215 Geneva, Switzerland.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Blasco
authors.affiliation: Medicines for Malaria Venture , 1215 Geneva, Switzerland.
authors.forename: Emilie
authors.initials: E
authors.lastname: Rossignol
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: Dave
authors.initials: D
authors.lastname: Matthews
authors.affiliation: Medicines for Malaria Venture , 1215 Geneva, Switzerland.
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Burrows
authors.affiliation: Medicines for Malaria Venture , 1215 Geneva, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Waterson
authors.affiliation: Medicines for Malaria Venture , 1215 Geneva, Switzerland.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Palmer
authors.affiliation: Departments of Chemistry and Global Health, University of Washington , Seattle, Washington 98195, United States.
authors.forename: Pradipsinh K
authors.initials: PK
authors.lastname: Rathod
authors.affiliation: Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, VIC 3052, Australia.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Charman
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000493:pharmacokinetics; D000090722:Dihydroorotate Dehydrogenase; D004285:Dogs; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000469:parasitology / Q000517:prevention & control*; D051379:Mice; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors; D015800:Protozoan Proteins; D011743:Pyrimidines; D044925:Oxidoreductases Acting on CH-CH Group Donors; C030986:pyrimidine
keywords: Plasmodium; dihydroorotate dehydrogenase; malaria; pyrimidine biosynthesis