Identification of a Metabolically Stable Triazolopyrimidine-Based Dihydroorotate Dehydrogenase Inhibitor with Antimalarial Activity in Mice
| Autor: | Sharon A. Creason, Farah El Mazouni, Margaret A. Phillips, Alka Marwaha, Karen L. White, Pradip Rathod, John H. White, David M. Shackleford, Susan A. Charman, Ramesh Gujjar, Jeffrey Baldwin, Frederick S. Buckner, William N. Charman |
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| Rok vydání: | 2009 |
| Předmět: |
Male
Models Molecular Oxidoreductases Acting on CH-CH Group Donors Plasmodium berghei Plasmodium falciparum Dihydroorotate Dehydrogenase Administration Oral In Vitro Techniques Pharmacology Article Antimalarials Mice Structure-Activity Relationship Parasitic Sensitivity Tests In vivo parasitic diseases Drug Discovery Animals Humans Structure–activity relationship Potency Dihydroorotate Dehydrogenase Inhibitor biology Chemistry Triazoles biology.organism_classification In vitro Malaria Thiazoles Pyrimidines Biochemistry Microsomes Liver Dihydroorotate dehydrogenase Molecular Medicine |
| Zdroj: | Journal of Medicinal Chemistry. 52:1864-1872 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm801343r |
| Popis: | Plasmodium faliciparum 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 anti-malarial chemotherapy. |
| Databáze: | OpenAIRE |
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