Specificity and reactivity of human leukocyte elastase, porcine pancreatic elastase, human granulocyte cathepsin G, and bovine pancreatic chymotrypsin with arylsulfonyl fluorides. Discovery of a new series of potent and specific irreversible elastase inhibitors.

The reactivity and specificity of a series of substituted benzenesulfonyl fluorides with human leukocyte (HL) elastase, cathepsin G, porcine pancreatic (PP) elastase, and bovine chymotrypsin A alpha are reported. Benzenesulfonyl fluorides with 2-fluoroacyl substituents were found to be potent and specific inhibitors of elastase. HL elastase was inhibited most rapidly by 2--(CF3CF2CONH)--C6H4SO4F (kobs/[I] = 1700 M-1 s-1) which is slightly better than our best peptide chloromethyl ketone inhibitor of this enzyme. PP elastase was most rapidly inhibited by 2--(CF3CONH)--C6H4-SO2F (kobs/[I] = 2300 M-1S-1). The 2--(CF3CF2CF2CONH) and 2--(CF3SNH) derivatives were quite selective for HL elastase and inhibited PP elastase, cathepsin G, and chymotrypsin A alpha quite slowly. A specific and potent chymotrypsin inhibitor (2--(Z--Gly--NH)--C6H4SO2F) was also discovered. A model for the elastase inhibition reaction is proposed which involves interaction of the fluroacyl group of the inhibitor with the primary substrate recognition site S1 of the enzyme. Hydrogen bonding also occurs between the inhibitor NH and a backbone peptide carbonyl group, probably from residue 214. The 2-fluoroacyl group plays the dual role of binding in the hydrophobic S1 pocket and through electronic effects, increasing the strength f the hydrogen bond. The results of this study demonstrate that it is possible to construct simple organic molecules which are specific inhibitors of HL elastase, PP elastase, or chymotrypsin.