NONPEPTIDIC INHIBITORS OF HUMAN-LEUKOCYTE ELASTASE .2. DESIGN, SYNTHESIS, AND IN-VITRO ACTIVITY OF A SERIES OF 3-AMINO-6-ARYLOPYRIDIN-2-ONETRIFLUOROMETHYL KETONES

A series of potent nonpeptidic inhibitors of the enzyme human leukocyt e elastase (HLE) is reported. These inhibitors contain a 3-amino-2-pyr idone ring as a central template in which the pyridone carbonyl and 3- position NH group are thought to form important hydrogen bonding inter actions with the Val-216 residue of HLE. Substitution of the 6-positio n of the pyridone ring by various alkyl and aryl groups was found to a fford increases in the in vitro potency of these inhibitors. A 6-posit ion phenyl group, compound 10f, was found to result in a large increas e in binding affinity, which was not obtained when the phenyl group wa s placed in either the 4- or 5-position of the molecule. Compound 10f was found to have good selectivity for HLE over other proteolytic enzy mes, with the exception of bovine pancreatic chymotrypsin (BPC). Subst itution of the 6-phenyl group in these molecules was found to decrease binding affinity for BPC without adversely affecting affinity for HLE .