Identification of a metabolically stable triazolopyrimidine-based dihydroorotate dehydrogenase inhibitor with antimalarial activity in mice

Ramesh Gujjar, Alka Marwaha, Farah El Mazouni, John White, Karen L. White, Sharon Creason, David M. Shackleford, Jeffrey Baldwin, William N. Charman, Frederick S. Buckner, Susan Charman, Pradipsinh K. Rathod, Margaret A. Phillips

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Abstract

Plasmodium falciparum causes 1-2 million deaths annually. Yet current drug therapies are compromised by resistance. We previously described potent and selective triazolopyrimidine-based inhibitors of P. falciparum dihydroorotate dehydrogenase (PfDHODH) that inhibited parasite growth in vitro; however, they showed no activity in vivo. Here we show that lack of efficacy against P. berghei in mice resulted from a combination of poor plasma exposure and reduced potency against P. berghei DHODH. For compounds containing naphthyl (DSM1) or anthracenyl (DSM2), plasma exposure was reduced upon repeated dosing. Phenyl-substituted triazolopyrimidines were synthesized leading to identification of analogs with low predicted metabolism in human liver microsomes and which showed prolonged exposure in mice. Compound 21 (DSM74), containing p-trifluoromethylphenyl, suppressed growth of P. berghei in mice after oral administration. This study provides the first proof of concept that DHODH inhibitors can suppress Plasmodium growth in vivo, validating DHODH as a new target for antimalarial chemotherapy.

Original languageEnglish (US)
Pages (from-to)1864-1872
Number of pages9
JournalJournal of Medicinal Chemistry
Volume52
Issue number7
DOIs
Publication statusPublished - Apr 9 2009

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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