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Identification of a metabolically stable triazolopyrimidine-based dihydroorotate dehydrogenase inhibitor with antimalarial activity in mice.
Title | Identification of a metabolically stable triazolopyrimidine-based dihydroorotate dehydrogenase inhibitor with antimalarial activity in mice. |
Publication Type | Journal Article |
Year of Publication | 2009 |
Authors | Gujjar, R, Marwaha, A, El Mazouni, F, White, J, White, KL, Creason, S, Shackleford, DM, Baldwin, J, Charman, WN, Buckner, FS, Charman, S, Rathod, PK, Phillips, MA |
Journal | J Med Chem |
Volume | 52 |
Issue | 7 |
Pagination | 1864-72 |
Date Published | 2009 Apr 9 |
ISSN | 1520-4804 |
Keywords | Administration, Oral, Animals, Antimalarials, Humans, Malaria, Male, Mice, Microsomes, Liver, Models, Molecular, Oxidoreductases Acting on CH-CH Group Donors, Parasitic Sensitivity Tests, Plasmodium berghei, Plasmodium falciparum, Pyrimidines, Structure-Activity Relationship, Thiazoles, Triazoles |
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. |
DOI | 10.1021/jm801343r |
Alternate Journal | J. Med. Chem. |
PubMed ID | 19296651 |