New orally active serine protease inhibitors: structural requirements for their good oral activity

Synthesis and structural requirements for good oral activity of a series of para-substituted benzoyl esters of 4-hydroxybenzamidine serine protease inhibitors are described. The structure required for good oral activity was found to be general formula II whose corresponding ester has to be hydrolyzed in the intestine before absorption through the mucous membranes or in plasma after absorption. Biological evaluation of oral absorption using plasma anti-trypsin activity was useful for rapid evaluation. By measuring their actual plasma concentrations after oral administration, compounds 14 and 16b were confirmed to show good area under the plasma concentration-time curves (AUC). Their plasma concentrations corresponded to their plasma anti-trypsin activity. Structure-oral activity relationships are discussed.