ORALLY-ACTIVE TRIFLUOROMETHYL KETONE INHIBITORS OF HUMAN-LEUKOCYTE ELASTASE

This paper describes the development a series of peptidyl trifluoromet hyl ketone inhibitors of human leukocyte elastase which are found to h ave excellent pharmacological profiles. Methods have been developed th at allow for the synthesis of these inhibitors in stereochemically pur e form. Two of these compounds, Ik and 1l, have high levels of oral bi oavailability in several species. Compound 1l has entered development as ZD8321 and is presently undergoing clinical evaluation. These compo unds demonstrate that peptidyl trifluoromethyl ketone inhibitors can a chieve high levels of oral activity and bioavailability, and therefore they may prove useful as therapeutic agents in the treatment of disea ses in which elastase is implicated.