title: Studies on (H(+)-K+)-ATPase inhibitors of gastric acid secretion. Prodrugs of 2-[(2-pyridinylmethyl)sulfinyl]benzimidazole proton-pump inhibitors.
abstract: The synthesis of N-substituted benzimidazole (H(+)-K+)-ATPase or proton-pump inhibitors is described. These compounds were prepared to function as prodrugs of the parent N-H compound and evaluated for their ability to inhibit gastric (H(+)-K+)-ATPase and gastric acid secretion. The prodrugs reported rely on either in vivo esterase hydrolysis for liberation of the parent compound (type I and type II) or require an acid environment for release of the active drug (type III and type IV). The N-(acyloxy)alkyl-substituted benzimidazoles 9, 11, and 24 showed improved chemical stability in the solid state and in aqueous solutions when compared to their parent N-H compounds. When given orally, 24 was found to be twice as potent as omeprazole in both the Shay rat and inactivation of gastric (H(+)-K+)-ATPase in the rat. The N-ethoxy-1-ethyl-substituted benzimidazoles 48-50 were found equally as effective as the N-H compound for inhibition of rat (H(+)-K+)-ATPase activity. In the Shay rat 48 at 10 mg/kg was approximately twice as active as parent timoprazole.
authors.affiliation: Research Laboratories, Upjohn Company, Kalamazoo, Michigan 49001.
authors.forename: J C
authors.initials: JC
authors.lastname: Sih
authors.forename: W B
authors.initials: WB
authors.lastname: Im
authors.forename: A
authors.initials: A
authors.lastname: Robert
authors.forename: D R
authors.initials: DR
authors.lastname: Graber
authors.forename: D P
authors.initials: DP
authors.lastname: Blakeman
mesh_terms: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors*; D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D004355:Drug Stability; D004950:Esterases / Q000378:metabolism; D005260:Female; D005744:Gastric Acid / Q000378:metabolism*; D005753:Gastric Mucosa / Q000201:enzymology; D017506:H(+)-K(+)-Exchanging ATPase; D006863:Hydrogen-Ion Concentration; D008297:Male; D015394:Molecular Structure; D009853:Omeprazole / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis*; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D013552:Swine
chemical_list: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D001562:Benzimidazoles; D011355:Prodrugs; C038402:timoprazole; D004950:Esterases; D000251:Adenosine Triphosphatases; D017506:H(+)-K(+)-Exchanging ATPase; D009853:Omeprazole