Journal of Medicinal Chemistry p. 4906 - 4916 (1995)
Update date:2022-09-26
Topics:
Kuhler
Fryklund
Bergman
Weilitz
Lee
Larsson
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 pK(a)-value of the pyridine, the pK(a)-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 β- 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 μmol/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 μmol/kg omeprazole b.i.d. for 4 weeks. Neither treatment proved efficacious.
View MoreLandz International Company Ltd.
Contact:0086-21-58891610
Address:985 Dongfang Road, Pudong, Shanghai 200122 China
Nanjing lanbai chemical Co.,Ltd.
Contact:+86-25-85499326
Address:Room 908, 9F Taiyue Building,No.285 Heyan Road
jiangsu senxuan pharmaceutical and chemical co.,ltd
Contact:86-523-87982810
Address:hongqiao industrial zone,taixing,jiangsu china
Xinji City Taida Sinopec Co., Ltd.
Contact:0086-311-85341278
Address:No.6, Nanhua Road,Xinji City Road,Hebei Province,China
Shanghai Yingrui Biopharma Co., Ltd
Contact:021-3358 8661*8003
Address:shanghai
Doi:10.1016/S0040-4039(00)88137-X
(1983)Doi:10.1016/j.tet.2008.02.074
(2008)Doi:10.1016/S0040-4020(01)96691-8
(1985)Doi:10.1021/jo00365a038
(1986)Doi:10.1139/v63-370
(1963)Doi:10.1016/j.tetlet.2008.02.162
(2008)