Human leukocyte elastase ynenol lactone inhibitors

A series of ynenol lactones (stmcture 2) were studied as inhibitors of human leukocyte elastase (Tam et al., 1984 Spencer et al., 1986 Copp et al., 1987). Some of the compounds were alternate substrate inhibitors, being hydrolyzed by the enzyme to the reactive I but then deacylat-ing without an inactivation step. However, with the compound 3-benzyl ynenol butyrolactone (stmcture 2, where R = benzyl, R = H), the acyl-enzyme (E-I ) was stable enough to allow the second alkylation step, resulting in inactivated enzyme. All kinetic constants were determined. Continuous assays gave biphasic kinetics, the second minor phase possibly due to the presence of isozymes or enantiomers of the inhibitor. Immediate diffusion-limited inhibition was observed and gave a competitive Ki value of 4.3 0.7 xM. The first phase of inhibition was saturable, and analysis of the rates gave = 0.090 0.007 s , and... 

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