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 (Book)Otherpeer-review

1 Citation (Scopus)

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
Title of host publicationComprehensive Medicinal Chemistry III
Subtitle of host publicationCase Histories in Recent Drug Discovery
EditorsSamuel Chackalamannil, David Rotella, Simon E Ward
Place of PublicationAmsterdam The Netherlands
PublisherElsevier
Chapter8.22
Pages544-557
Number of pages14
Volume8
Edition3
ISBN (Electronic)9780128032008
ISBN (Print)9780128032015
DOIs
Publication statusPublished - 3 Jun 2017

Publication series

NameReference Module in Chemistry, Molecular Sciences and Chemical Engineering
PublisherElsevier
Number3
Volume8

Keywords

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

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 S. Chackalamannil, D. Rotella, & S. E. Ward (Eds.), Comprehensive Medicinal Chemistry III: Case Histories in Recent Drug Discovery (3 ed., Vol. 8, pp. 544-557). (Reference Module in Chemistry, Molecular Sciences and Chemical Engineering; Vol. 8, No. 3). Elsevier. https://doi.org/10.1016/B978-0-12-409547-2.12470-9