STRUCTURE-ACTIVITY RELATIONSHIP OF OMEPRAZOLE AND ANALOGS AS HELICOBACTER-PYLORI UREASE INHIBITORS

Helicobacter pylori urease belongs to a family of highly conserved ure a-hydrolyzing enzymes. A common feature of these enzymes is the presen ce of two Lewis acid nickel ions and a reactive cysteine residue in th e active site. The H+/K+-ATPase inhibitor omeprazole is a prodrug of a sulfenamide which covalently modifies cysteine residues on the lumina l side of the H+/K+-ATPase of gastric parietal cells., Omeprazole and eight analogues were selected based on their chemical, electronic, and kinetic properties, and each was incubated with viable H. pylori in p hosphate-buffered saline at pH 7.4 for 30 min, after which 100 mM urea was added and the amount of ammonia formed analyzed after a further 1 0 min. Inhibition between 0% and 100% at a 0.1 mM concentration was ob served for the different analogues and could be expressed as a functio n of the pK(a)-value of the pyridine, the pK(a)-value of the benzimida zole, the overall lipophilicity, and, most importantly, the rate of su lfenamide formation, in a quantitative structure-activity relationship . The inhibition was potentiated by a lower pH (favoring the formation of the sulfenamide) but abolished in the presence of beta-mercaptoeth anol (a scavenger of the sulfenamide). Structural analogues incapable of yielding the sulfenamide did not inhibit ammonia production. Treatm ent of Helicobacter felis-infected mice with 230 mu mol/kg flufofamide b.i.d. for 4 weeks, known to potently inhibit urease activity in vivo , as a means of eradicating the infection, was tested and compared wit h the effect of 125 mu mol/kg omeprazole b.i.d. for 4 weeks. Neither t reatment proved efficacious.