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

Previous studies in rats and humans demonstrated poor oral bioavailability of potent in vitro 2-aminobenzimidazole inhibitors of rhinovirus replicatio n due to significant first-pass elimination and possibly also to poor aqueo us solubility. Estimations of aqueous solubility, as well as measurements o f caco-2 permeability and NADPH dependent compound loss in rat liver micros omal incubations were employed alongside traditional in vivo experiments in rats to guide subsequent chemistry efforts. Retention of activity upon rep lacement 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 independe ntly measure solubility, permeability, and metabolic stability of new compo unds, variable solubility across the series (ranging from approximately 1 t o 10 mu g/mL) was identified as the cause of the inconsistent performance. Subsequent efforts to improve solubility led to the discovery of highly sol uble (>10 mg/mL) and potent dessulfonyl vinyl carboxamide benzimidazoles. D etermination of the metabolic stability of these compounds as a surrogate o f the extent of their first-pass elimination supported a prediction of exce llent oral bioavailability. In comparison to the sulfonyl-containing vinyl carboxamides, caco-2 permeabilities were reduced 5 to 10-fold; however, the se were considered to be in the range of well-absorbed compounds based on c omparison to a series of reference compounds of known percentage absorption in humans. Subsequent experiments in the rat verified the oral bioavailabi lity of these N-alkyl compounds, with one compound (368177) having an absol ute oral bioavailability of 89.4%. The application of solubility and caco-2 permeability as surrogates for oral absorption potential, in conjunction w ith the use of microsomal incubations as a surrogate for first-pass metabol ism, was shown to augment a rational, chemistry approach to discover orally bioavailable inhibitors of rhinovirus replication. Future expanded use of these surrogates is planned.