Structure-activity relationship of omeprazole and analogues as Helicobacter pylori urease inhibitors.
Helicobacter pylori urease belongs to a family of highly conserved urea-hydrolyzing enzymes. A common feature of these enzymes is the presence of two Lewis acid nickel ions and a reactive cysteine residue in the active site. The H+/K(+)-ATPase inhibitor omeprazole is a prodrug of a sulfenamide which covalently modifies cysteine residues on the luminal 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 phosphate-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 10 min. Inhibition between 0% and 100% at a 0.1 mM concentration was observed for the different analogues and could be expressed as a function of the pKa-value of the pyridine, the pKa-value of the benzimidazole, the overall lipophilicity, and, most importantly, the rate of sulfenamide 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-mercaptoethanol (a scavenger of the sulfenamide). Structural analogues incapable of yielding the sulfenamide did not inhibit ammonia production. Treatment of Helicobacter felis-infected mice with 230 mumol/kg flurofamide 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 with the effect of 125 mumol/kg omeprazole b.i.d. for 4 weeks. Neither treatment proved efficacious.
Kühler
T C
TC
Department of Medicinal Chemistry, Astra Hässle AB, Mölndal, Sweden.
Fryklund
J
J
Bergman
N A
NA
Weilitz
J
J
Lee
A
A
Larsson
H
H
D000641:Ammonia / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D000897:Anti-Ulcer Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects; D003545:Cysteine / Q000187:drug effects; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D016480:Helicobacter pylori / Q000187:drug effects / Q000201:enzymology*; D006863:Hydrogen-Ion Concentration; D008623:Mercaptoethanol / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D009853:Omeprazole / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014510:Urease / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000900:Anti-Bacterial Agents; D000897:Anti-Ulcer Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; C032764:flurofamide; D008623:Mercaptoethanol; D000641:Ammonia; D014510:Urease; D003545:Cysteine; D009853:Omeprazole