Absorption, distribution, metabolism, and excretion considerations in selection of orally active indole-containing endothelin antagonist

A series of potent indole-containing endothelin antagonists were evaluated in rat pharmacokinetic studies as part of a rational drug design program. E arly compounds in this series were found to show poor gastrointestinal abso rption, limiting their utility as oral agents. Structural modifications and pharmacokinetic studies indicated that reducing the overall H-bonding pote ntial, through a reduction in the number of H-bond donors and acceptors, co uld increase absorption of the molecules. There was a correlation between c alculated H-bonding capacity and rate of permeability across Caco-2 monolay ers for this series of compounds. Caco-2 permeability was also shown to be indicative of the estimated extent of absorption in rats. Balancing the req uirements of absorption and systemic clearance lead to the selection of an alcohol-containing compound, compound 7a (single enantiomer of compound 7) that was moderately absorbed after oral administration and converted to an active acid metabolite, which itself was of low intrinsic clearance. Specie s differences were observed between the absorption of compound 7a in rat an d dog and also in the extent of conversion to the acid metabolite. Absorpti on was estimated at 30% in rat and 100% in dog. Approximately 30% of the ab sorbed drug was converted to systemically available acid metabolite in rat, compared with only 3% in dog.