H,K ATPase inhibitors

Gastric H,K-ATPase inhibitors Potassium competitive acid blockers... 

GABA, heterocyclic analogues, 22 (1985) 67 GABAa receptor ligands, 36 (1999) 169 Gas-liquid chromatography and mass spectrometry, 12 (1975) 1 Gastric H /K -ATPase inhibitors, 31 (1994) 233... 

Other proton pump inhibitors e.g., lansoprazole is more potent than omeprazole and has higher bioavailability, rapid onset of action and longer duration of action. Pantoprazole is the new H+K+ATPase inhibitor with similar properties and action to omeprazole. 

A hexaprenyl-hydroquinone sulfate (395) was identified as an H+/K+-ATPase inhibitor from a Japanese species of Dysidea [339]. Sarcotragus spinulosus from deep water contained the Na+/K+-ATPase inhibitors sarcochromenol sulfates A-C (396-398) and sarcohydroquinone sulfates A-C (399-401) [340]. The structures were determined by spectral data analysis of the natural products and of derivatives. 

Ife RJ, Dyke CA, Keeling DJ, Meenan E, Meeson ML, Parsons ME, et al. 2-[[(4-Amino-2-pyridyl)methyl]sulfinyl]-benzimidazole H+/K+-ATPase inhibitors. The relationship between pyridine basicity, stability, and activity. /. Med. Chem., 1989, 32(8), 1970-1977. 

For the specific pharmacological assessment of inhibitors of gastric acid secretion, like H2-blockers, anticholinergics, H+/K+-ATPase inhibitors, this method reveals valid results with respect to the antisecretory potential of the candidate compound. Limitations of this methods with respect to safety pharmacological assessment of candidate compounds are (1) only parenteral administration of the candidate compound, preferentially i.v., is feasible and should be preferred, and (2) only antisecretory putative side effects can be investigated this method is of limited relevance to study secretory side effect potential of candidate compounds. 

Herling and Bickel (1986) showed that gastric acid secretion in stomach-lumen perfused rats can be stimulated in vivo on the subreceptor level by IBMX (phosphodiesterase inhibitor) and forskolin (non-receptor activation of the adenylate cyclase). H+/K+-ATPase inhibitors and H2-antagonists show, according to their different modes of action, also a different inhibitory profile in this assay. 

Herling AW, Bickel M, Lang HJ, Weidmann K, Rosner M, Metzger H, Rippel R, Nimmesgem H Scheunemann KH (1988) A substituted thienol[3.4-d]imidazole versus substituted benzimida-zoles as H+,K+-ATPase inhibitors. Pharmacology 36 289-297... 

H2-receptor antagonists are quite effective in some peptic acid disorders (duodenal ulcers, gastric ulcers), whereas their effectiveness in others is less apparent (Zollinger-Ellison syndrome, gastrooesophageal reflux disease) [22]. For such conditions, prolonged and potent reduction of acid secretion caused by H /K -ATPase inhibitors is necessary and results in superiority of omeprazole over H2-receptor antagonists [25, 26]. 

The effect of gastric HVK -ATPase inhibitors on enzyme activity (ATP cleavage) can be studied in vitro with partly purified HVK -ATPase preparations [27]. This assay has been used more effectively to study the mechanism of action of H /K -ATPase inhibitors in detail than to study the structure-activity relationship of such inhibitors [28]. Since HVK -ATPase inhibitors of the omeprazole-type need acid activation and the enzyme assay should be performed at neutral pH values, a pre-incubation period at the lowest possible pH of about 6 was used to initiate the acidic conversion of the test compound into its active principle. This reflects more the chemical instability of the test compound at neutral pH values than its effect during conditions of much higher acidity within the secretory cannaliculus of the parietal cell during acid secretion. Many chemically labile inhibitors are therefore very active in this test system. However, they do not cause an inhibition in more complex test systems and, therefore, are without any practical usefulness [28]. 

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