Application of oral bioavailability surrogates in the design of orally active inhibitors of rhinovirus replication

Robert E. Stratford, Michael P. Clay, Beverly A. Heinz, Michael T. Kuhfeld, Stacy J. Osborne, Diane L. Phillips, Stephanie A. Sweetana, Mark J. Tebbe, Vasu Vasudevan, Larry L. Zornes, Terry D. Lindstrom

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11 Scopus citations


Previous studies in rats and humans demonstrated poor oral bioavailability of potent in vitro 2-aminobenzimidazole inhibitors of rhinovirus replication due to significant first-pass elimination and possibly also to poor aqueous solubility. Estimations of aqueous solubility, as well as measurements of caco-2 permeability and NADPH dependent compound loss in rat liver microsomal incubations were employed alongside traditional in vivo experiments in rats to guide subsequent chemistry efforts. Retention of activity upon replacement of the metabolically labile vinyl oxime in the lead molecule with a vinyl carboxamide was a major breakthrough; however, oral bioavailability among the latter compounds was variable. Based on the ability to independently measure solubility, permeability, and metabolic stability of new compounds, variable solubility across the series (ranging from approximately 1 to 10 μg/mL) was identified as the cause of the inconsistent performance. Subsequent efforts to improve solubility led to the discovery of highly soluble (>10 mg/mL) and potent dessulfonyl vinyl carboxamide benzimidazoles. Determination of the metabolic stability of these compounds as a surrogate of the extent of their first-pass elimination supported a prediction of excellent oral bioavailability. In comparison to the sulfonyl- containing vinyl carboxamides, caco-2 permeabilities were reduced 5 to 10- fold; however, these were considered to be in the range of well-absorbed compounds based on comparison to a series of reference compounds of known percentage absorption in humans. Subsequent experiments in the rat verified the oral bioavailability of these N-alkyl compounds, with one compound (368177) having an absolute oral bioavailability of 89.4%. The application of solubility and caco-2 permeability as surrogates for oral absorption potential, in conjunction with the use of microsomal incubations as a surrogate for first-pass metabolism, was shown to augment a rational chemistry approach to discover orally bioavailable inhibitors of rhinovirus replication. Future expanded use of these surrogates is planned.

Original languageEnglish (US)
Pages (from-to)747-753
Number of pages7
JournalJournal of Pharmaceutical Sciences
Issue number8
StatePublished - Aug 1999
Externally publishedYes

ASJC Scopus subject areas

  • Pharmaceutical Science

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    Stratford, R. E., Clay, M. P., Heinz, B. A., Kuhfeld, M. T., Osborne, S. J., Phillips, D. L., Sweetana, S. A., Tebbe, M. J., Vasudevan, V., Zornes, L. L., & Lindstrom, T. D. (1999). Application of oral bioavailability surrogates in the design of orally active inhibitors of rhinovirus replication. Journal of Pharmaceutical Sciences, 88(8), 747-753.