In Vitro Metabolism of Phenoxypropoxybiguanide Analogues in Human Liver Microsomes to Potent Antimalarial Dihydrotriazines
| Autor: | Michael P. Kozar, Todd W Shearer, Guy A. Schiehser, David P. Jacobus, Wilbur K. Milhous, Philip L. Smith, Michael T. O’Neil, Young-Sun Yang, Damaris S. Diaz, Donald R. Skillman |
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| Rok vydání: | 2005 |
| Předmět: | |
| Zdroj: | Journal of Medicinal Chemistry. 48:2805-2813 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | Phenoxypropoxybiguanides, such as 1 (PS-15), are prodrugs analogous to the relationship of proguanil and its active metabolite cycloguanil. Unlike cycloguanil, however, 1a (WR99210), the active metabolite of 1, has retained in vitro potency against newly emerging antifolate-resistant malaria parasites. Unfortunately, manufacturing processes and gastrointestinal intolerance have prevented the clinical development of 1. In vitro antimalarial activity and in vitro metabolism studies have been performed on newly synthesized phenoxypropoxybiguanide analogues. All of the active dihydrotriazine metabolites exhibited potent antimalarial activity with in vitro IC50 values less than 0.04 ng/mL. In vitro metabolism studies in human liver microsomes identified the production of not only the active dihydrotriazine metabolite, but also a desalkylation on the carbonyl chain, and multiple hydroxylated metabolites. The Vmax for production of the active metabolites ranged from 10.8 to 27.7 pmol/min/mg protein with the Km r... |
| Databáze: | OpenAIRE |
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