Wc. Groutas et al., MECHANISM-BASED INHIBITION OF HUMAN-LEUKOCYTE ELASTASE AND CATHEPSIN-G BY SUBSTITUTED DIHYDROURACILS, Biochimica et biophysica acta. Molecular basis of disease, 1227(3), 1994, pp. 130-136
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.