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ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Amino Acid Ester Prodrugs of 2-Bromo-5,6-dichloro-1-(-D-ribofuranosyl)benzimidazole Enhance Metabolic Stability in Vitro and in Vivo

Departments of Pharmaceutical Sciences (P.L.L., C.P.L., X.S., G.L.A.) and Medicinal Chemistry (L.B.T., J.C.D.), College of Pharmacy, and Department of Biologic and Materials Sciences (K.Z.B., J.M.B., J.C.D.), School of Dentistry, University of Michigan, Ann Arbor, Michigan; and Therapeutic Systems Research Laboratories, Inc. (J.S.K., J.M.H.), Ann Arbor, Michigan

2-Bromo-5,6-dichloro-1-(-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.

Address correspondence to: Dr. Gordon L. Amidon, Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, 428 Church St., Ann Arbor, MI 48109-1065. E-mail: glamidon{at}umich.edu

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