NONPEPTIDIC INHIBITORS OF HUMAN-LEUKOCYTE ELASTASE .4. DESIGN, SYNTHESIS, AND IN-VITRO AND IN-VIVO ACTIVITY OF A SERIES OF BETA-CARBOLINONE-CONTAINING TRIFLUOROMETHYL KETONES

A novel series of human leukocyte elastase (HLE) inhibitors containing the beta-carbolinone ring system are reported. The design of these tr ifluoromethyl ketone-based inhibitors used a combination of structural information obtained from X-ray crystallography and molecular modelin g investigations. The beta-carbolinone ring in these compounds serves as a highly efficient peptidiomimetic for the P-2-P-3 region of peptid yl trifluoromethyl ketone inhibitors of HLE. Several of the beta-carbo linones exhibit significant in vitro potency, with K-i values in the n anomolar recognition of these inhibitors by HLE have been obtained and are discussed. This series of compounds are found to have excellent s electivity for HLE over a number of other proteolytic enzymes, includi ng closely related enzymes such as porcine pancreatic elastase.