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Title: A Triazolopyrimidine-Based Dihydroorotate Dehydrogenase Inhibitor with Improved Drug-like Properties for Treatment and Prevention of Malaria

Journal Article · · ACS Infectious Diseases
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  1. Univ. of Texas Southwestern Medical Center, Dallas, TX (United States)
  2. Monash Univ., Melbourne, VIC (Australia)
  3. Univ. of Washington, Seattle, WA (United States). Dept. of Chemistry
  4. AbbVie Inc., North Chicago, IL (United States)
  5. Syngene International Ltd., Bangalore (India)
  6. Charles Darwin Univ., Casuarina, NT (Australia)
  7. Eijkman Inst. for Molecular Biology, Jakarta (Indonesia)
  8. Charles Darwin Univ., Casuarina, NT (Australia); Univ. of Oxford (United Kingdom)
  9. GlaxoSmithKline, Madrid (Spain)
  10. Centre Suisse de Recherches Scientifiques en Côte d’Ivoire (Ivory Coast)
  11. Biomedical Primate Research Centre, Rijswijk (The Netherlands)
  12. Medicines for Malaria Venture, Geneva (Switzerland)
+ Show Author Affiliations

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.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
USDOE Office of Science (SC)
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
1335991
Journal Information:
ACS Infectious Diseases, Vol. 2, Issue 12; ISSN 2373-8227
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 63 works
Citation information provided by
Web of Science

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Cited By (10)

The resistome and genomic reconnaissance in the age of malaria elimination journal December 2019
Synthesis, Design, and Structure–Activity Relationship of the Pyrimidone Derivatives as Novel Selective Inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase journal May 2018
Enhanced Ex Vivo Plasmodium vivax Intraerythrocytic Enrichment and Maturation for Rapid and Sensitive Parasite Growth Assays journal January 2018
UCT943, a Next-Generation Plasmodium falciparum PI4K Inhibitor Preclinical Candidate for the Treatment of Malaria journal June 2018
Chemical structure modifications and nano-technology applications for improving ADME-Tox properties, a review journal January 2019
Malaria journal August 2017
An in vitro toolbox to accelerate anti-malarial drug discovery and development journal January 2020
The Development of Novel Compounds Against Malaria: Quinolines, Triazolpyridines, Pyrazolopyridines and Pyrazolopyrimidines journal November 2019
Efficient and regioselective one-step synthesis of 7-aryl-5-methyl- and 5-aryl-7-methyl-2-amino-[1,2,4]triazolo[1,5-a]pyrimidine derivatives journal January 2017
UCT943, a next generation Plasmodium falciparum PI4K inhibitor preclinical candidate for the treatment of malaria text January 2018

Figures / Tables (10)

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Related Subjects

60 APPLIED LIFE SCIENCES
malaria
Plasmodium
pyrimidine biosynthesis
dihydroorotate dehydrogenase