Urease Inhibitors for Hepatic Coma. II. Comparative Efficacy of Four Lower Hydroxamate Homologs in Vitro and in Vivo 1

Abstract

Summary

Formo- (FHA), aceto- (AHA), propiono- (PHA), and isobutyro- (IBHA) hydroxamic acids have been evaluated as inhibitors of jackbean urease in vitro and of bacterial urease in male CAF₁ mice. All four were active throughout the pH range 5–9, bound tightly to the enzyme as manifested by K_I values of 4 μM or less, and exhibited low association rate constants for the formation of EI complex. The development of inhibition was kinetically irreversible for all of the compounds except FHA, but this is believed to represent simply the operational effect of low rate and equilibrium dissociation constants, rather than a true organochemical alteration of the enzyme. In mice the ED₅₀ for the inhibition of ureolysis during the first 2 hr after administration, in millimoles/per kilogram body weight, was 1.45 for FHA, 2.10 for AHA, 2.20 for PHA, and 5.35 for IBHA. Hydroxyurea was much inferior to any of these compounds as a urease inhibitor. The inhibition was maximum during the first 2 hr after administration in all cases; yet all, except PHA, demonstrated significant residual inhibition 16–22 hr later.