Document Detail

Chemistry of covalent inhibition of the gastric (H+, K+)-ATPase by proton pump inhibitors.
MedLine Citation:
PMID:  15212527     Owner:  NLM     Status:  MEDLINE    
Proton pump inhibitors (PPIs), drugs that are widely used for treatment of acid related diseases, are either substituted pyridylmethylsulfinyl benzimidazole or imidazopyridine derivatives. They are all prodrugs that inhibit the acid-secreting gastric (H(+), K(+))-ATPase by acid activation to reactive thiophiles that form disulfide bonds with one or more cysteines accessible from the exoplasmic surface of the enzyme. This unique acid-catalysis mechanism had been ascribed to the nucleophilicity of the pyridine ring. However, the data obtained here show that their conversion to the reactive cationic thiophilic sulfenic acid or sulfenamide depends mainly not on pyridine protonation but on a second protonation of the imidazole component that increases the electrophilicity of the C-2 position on the imidazole. This protonation results in reaction of the C-2 with the unprotonated fraction of the pyridine ring to form the reactive derivatives. The relevant PPI pK(a)'s were determined by UV spectroscopy of the benzimidazole or imidazopyridine sulfinylmethyl moieties at different medium pH. Synthesis of a relatively acid stable analogue, N(1)-methyl lansoprazole, (6b), allowed direct determination of both pK(a) values of this intact PPI allowing calculation of the two pK(a) values for all the PPIs. These values predict their relative acid stability and thus the rate of reaction with cysteines of the active proton pump at the pH of the secreting parietal cell. The PPI accumulates in the secretory canaliculus of the parietal cell due to pyridine protonation then binds to the pump and is activated by the second protonation on the surface of the protein to allow disulfide formation.
Jai Moo Shin; Young Moon Cho; George Sachs
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Journal of the American Chemical Society     Volume:  126     ISSN:  0002-7863     ISO Abbreviation:  J. Am. Chem. Soc.     Publication Date:  2004 Jun 
Date Detail:
Created Date:  2004-06-23     Completed Date:  2004-09-07     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  7503056     Medline TA:  J Am Chem Soc     Country:  United States    
Other Details:
Languages:  eng     Pagination:  7800-11     Citation Subset:  IM    
Department of Physiology and Medicine, University of California at Los Angeles, and VA Greater Los Angeles Healthcare System, Los Angeles, California 90073, USA.
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MeSH Terms
Anti-Ulcer Agents / chemistry,  pharmacology*
Benzimidazoles / chemistry,  metabolism
Drug Stability
Enzyme Inhibitors / chemistry*,  pharmacology
Gastric Acid / secretion
H(+)-K(+)-Exchanging ATPase / antagonists & inhibitors*,  chemistry,  metabolism
Heterocyclic Compounds, 2-Ring / chemical synthesis
Hydrogen-Ion Concentration
Models, Chemical
Proton Pumps / antagonists & inhibitors*
Spectrophotometry, Ultraviolet
Stomach / enzymology*
Grant Support
17294//PHS HHS; 41301//PHS HHS; 53462//PHS HHS; DK46917/DK/NIDDK NIH HHS
Reg. No./Substance:
0/Anti-Ulcer Agents; 0/Benzimidazoles; 0/Enzyme Inhibitors; 0/Heterocyclic Compounds, 2-Ring; 0/Proton Pumps; EC ATPase

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