Medicinal Chemistry Case History: Discovery of the Dihydroorate Dehydrogenase Inhibitor DSM265 as an Antimalarial Drug Candidate

M. A. Phillips, P. K. Rathod, T. Rueckle, D. Matthews, J. N. Burrows, S. A. Charman

Research output: Chapter in Book/Report/Conference proceedingChapter

1 Scopus citations

Abstract

Half of the globe remains at risk for malaria, yet drug resistance threatens current treatments. DSM265 was discovered through a target-based screen and subsequent structure-guided lead optimization, as a novel triazolopyrimidine-based inhibitor of Plasmodium dihydroorotate dehydrogenase (DHODH). DSM265 is the first antimalarial targeting DHODH and, due to its novel mechanism, is expected to function against Plasmodium species resistant to current chemotherapies. Key DSM265 characteristics include blood- and liver-stage activity, parasite selectivity, and a long human half-life, supporting its development as either a single dose treatment or once weekly prophylactic, in combination with a suitable partner to help prevent resistance.

Original languageEnglish (US)
Title of host publicationCase Histories in Recent Drug Discovery
PublisherElsevier Inc.
Pages544-557
Number of pages14
Volume8-8
ISBN (Electronic)9780128032008
ISBN (Print)9780128032015
DOIs
StatePublished - Jun 3 2017

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Keywords

  • Artemisinin.
  • DHODH.
  • Dihydroorotate dehydrogenase.
  • DSM265.
  • Malaria.
  • Plasmodium.
  • Pyrimidine.
  • Triazolopyrimidine

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

Phillips, M. A., Rathod, P. K., Rueckle, T., Matthews, D., Burrows, J. N., & Charman, S. A. (2017). Medicinal Chemistry Case History: Discovery of the Dihydroorate Dehydrogenase Inhibitor DSM265 as an Antimalarial Drug Candidate. In Case Histories in Recent Drug Discovery (Vol. 8-8, pp. 544-557). Elsevier Inc.. https://doi.org/10.1016/B978-0-12-409547-2.12470-9