6-Substituted 2-Oxo-2H-1-benzopyran-3-carboxylic Acid as a Core Structure for Specific Inhibitors of Human Leukocyte Elastase†

Pyridyl esters of 6-substituted 2-oxo-2H-1-benzopyran-3-carboxylic acid were designed as mechanism-based inhibitors of human leukocyte elastase. Compounds of series 4 specifically inhibited this enzyme. Several of the tested compounds (series 2 and 3) acted as powerful time-dependent inhibitors of both human leukocyte elastase and α-chymotrypsin; some compounds of these series inhibited thrombin. Trypsin was not inhibited. A transient inactivation was observed for human leukocyte elastase (ki/KI = 107 000 M-1·s-1 for 4c) and thrombin (ki/KI = 7 200 M-1·s-1 for 3b) as demonstrated by spontaneous or hydroxylamine-accelerated reactivation, irrespective of the nature of the substituent at the 6-position. Conversely, α-chymotrypsin was irreversibly inhibited by 6-chloromethyl derivatives (ki/KI = 107 400 M-1·s-1 for 3b). The presence of a latent alkylating function at the 6-position (chloromethyl group) was required for leading to this inactivation. In the absence of such an alkylating function (series 4), hum...