| Amino acid ester prodrugs of 2-bromo-5,6-dichloro-1-(beta-D-ribofuranosyl)benzimidazole enhance metabolic stability in vitro and in vivo. | |
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MedLine Citation:
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PMID: 15901797 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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2-Bromo-5,6-dichloro-1-(beta-d-ribofuranosyl)benzimidazole (BDCRB) is a potent and selective inhibitor of human cytomegalovirus (HCMV), but it lacks clinical utility due to rapid in vivo metabolism. We hypothesized that amino acid ester prodrugs of BDCRB may enhance both in vitro potency and systemic exposure of BDCRB through evasion of BDCRB-metabolizing enzymes. To this end, eight different amino acid prodrugs of BDCRB were tested for N-glycosidic bond stability, ester bond stability, Caco-2 cell uptake, antiviral activity, and cytotoxicity. The prodrugs were resistant to metabolism by BDCRB-metabolizing enzymes, and ester bond cleavage was rate-limiting in metabolite formation from prodrug. Thus, BDCRB metabolism could be controlled by the selection of promoiety. In HCMV plaque-formation assays, l-Asp-BDCRB exhibited 3-fold greater selectivity than BDCRB for inhibition of HCMV replication. This potent and selective antiviral activity in addition to favorable stability profile made l-Asp-BDCRB an excellent candidate for in vivo assessment and pharmacokinetic comparison with BDCRB. In addition to rapid absorption and sufficient prodrug activation after oral administration to mice, l-Asp-BDCRB exhibited a 5-fold greater half-life than BDCRB. Furthermore, the sum of area under the concentration-time profile (AUC)(BDCRB) and AUC(prodrug) after l-Asp-BDCRB administration was roughly 3-fold greater than AUC(BDCRB) after BDCRB administration, suggesting that a reservoir of prodrug was delivered in addition to parent drug. Overall, these findings demonstrate that amino acid prodrugs of BDCRB exhibit evasion of metabolizing enzymes (i.e., bioevasion) in vitro and provide a modular approach for translating this in vitro stability into enhanced in vivo delivery of BDCRB. |
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Authors:
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Philip L Lorenzi; Christopher P Landowski; Xueqin Song; Katherine Z Borysko; Julie M Breitenbach; Jae Seung Kim; John M Hilfinger; Leroy B Townsend; John C Drach; Gordon L Amidon |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, P.H.S. Date: 2005-05-18 |
Journal Detail:
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Title: The Journal of pharmacology and experimental therapeutics Volume: 314 ISSN: 0022-3565 ISO Abbreviation: J. Pharmacol. Exp. Ther. Publication Date: 2005 Aug |
Date Detail:
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Created Date: 2005-07-18 Completed Date: 2005-09-30 Revised Date: 2007-11-14 |
Medline Journal Info:
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Nlm Unique ID: 0376362 Medline TA: J Pharmacol Exp Ther Country: United States |
Other Details:
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Languages: eng Pagination: 883-90 Citation Subset: IM |
Affiliation:
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Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, MI 48109-1065. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antiviral Agents / pharmacokinetics, pharmacology* Benzimidazoles / pharmacokinetics, pharmacology* Caco-2 Cells Cell Survival / drug effects Chromatography, High Pressure Liquid Cytomegalovirus / drug effects* DNA Glycosylases / metabolism Female Humans Intestines / metabolism Liver / metabolism Mice Prodrugs / pharmacokinetics, pharmacology* Ribonucleosides / pharmacokinetics, pharmacology* |
| Grant Support | |
ID/Acronym/Agency:
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GM 07767/GM/NIGMS NIH HHS; P01 AI 46390/AI/NIAID NIH HHS; R01 GM 37188/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/2-bromo-5,6-dichloro-1-beta-D-ribofuranosyl benzimidazole; 0/Antiviral Agents; 0/Benzimidazoles; 0/Prodrugs; 0/Ribonucleosides; EC 3.2.2.-/DNA Glycosylases; EC 3.2.2.-/Ogg1 protein, mouse |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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