MECHANISM-BASED INHIBITION OF HUMAN-LEUKOCYTE ELASTASE AND CATHEPSIN-G BY SUBSTITUTED DIHYDROURACILS

A series of dihydrouracil derivatives has been synthesized and investi gated for their in vitro inhibitory activity toward human leukocyte el astase (HLE) and cathepsin G (Cath G). Alkyl [sulfonyl(oxy)] uracils 1 -2 were found to be efficient, time - dependent inhibitors of elastase (k(obs)/[I] M(-1) s(-1) values ranged between 480 and 8110). These co mpounds formed acyl enzymes that exhibited variable hydrolytic stabili ty which appeared to be dependent on the nature of the R(1) group (bel ieved to be accommodated at the primary specificity site, S-1). The ac yl enzymes formed with cathepsin G deacylated rapidly, leading to a si gnificant regain of enzymatic activity. In sharp contrast, the corresp onding phosphorus compounds 3-4 were found to be potent, time-dependen t irreversible inhibitors of HLE. Furthermore, the results of the stru cture-activity relationship studies suggest that the binding modes of compounds 1-2 and 3-4 may be different.