A series of 2-aryl-4,5-dihydro-1H-thieno[3,2-e]benzimidazoles (1, 2) was prepared by condensation of 5-acylamino-4,5,6,7-tetrahydrobenzo[b]thiophen-4-ones (9, 10) with ammonium acetate under azeotropic reaction conditions. Various congeners, N-methyl and N-phenyl analogues (3-5), 4,5-dihydro-1H-thieno[2,3-e]benzimidazoles (6), 4,5-dihydro-1H-thieno[2,3-g]benzoxazoles (7), and 4,5-dihydro-1H-thieno[2,3-g]benzothiazoles (8), were also prepared. Several compounds in this series were shown to be K(+)-competitive inhibitors of the gastric (H+/K+)-ATPase and more potent inhibitors than SK&F-96067, 3-butyryl-8-methoxy-4-(2-tolylamino)quinoline, on pentagastrin-stimulated acid secretion in chronic gastric fistula rats after intraduodenal administration.

01 Mar 1996·The Journal of pharmacology and experimental therapeutics

H+-K+ ATPase inhibitors cause relaxation of guinea pig and human airway smooth muscle in vitro.

Article

Author: Rhoden, K J ; Douglas, J S ; Tallini, G

The effect of H+-K+ ATPase inhibitors on airway smooth muscle tone was investigated in vitro. Four H+-K+ ATPase inhibitors, SCH 28080 (2-methyl-8-(phenylmethoxy)-imidazo[1,2-a] pyridine-3-acetonitrile), SK&F 96067 (3-butyryl-4-(2-methylphenylamino)-8-methoxy-quinoline), omaprezole (5-methoxy-2-(((4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl)-sulfinyl)-1H -benzimidazole) and NC-1300-B (2-(2-dimethylaminobenzylsulfiny)-5-methoxybenzimidazole), induced concentration-dependent relaxation of guinea pig trachea with spontaneous tone, with IC50 values of 5.9, 7.1, 155 and 79 microM, respectively, SCH 28080 and omeprazole also relaxed airways precontracted with carbachol or histamine in the presence of indomethacin. Relaxation was similar in intact and epithelium-denuded tracheal preparations, suggesting that the airway epithelium neither mediates or modulates relaxation induced by H+-K+ ATPase inhibitors. SCH 28080-induced relaxation was not influenced by tetrodotoxin, suggesting that it is not neurogenically mediated. Bafilomycin A1 and concanamycin A had no effect on guinea pig tracheal spontaneous tone, suggesting that relaxation induced by H+-K+ ATPase inhibitors is not due to an interaction with a vacuolar H+ ATPase. SCH 28080 also induced concentration-dependent relaxation of human bronchi precontracted with histamine. These results demonstrate that several structurally and/or mechanistically distinct H+-K+ ATPase inhibitors cause relaxation of airway smooth muscle in vitro, and suggest that a H+-K+ ATPase or similar pathway may play a role in the maintenance of airway smooth muscle tone.

01 Jun 1991·Biochemical Pharmacology

SK&F 96067 is a reversible, lumenally acting inhibitor of the gastric (H+ + K+)-ATPase

Article

Author: S.M. Laing ; C.A. Leach ; D.J. Keeling ; R.J. Ife ; R.C. Malcolm

SK&F 96067 [3-butyryl-4-(2-methylphenylamino)-8-methoxyquinoline] has been identified, from a novel class of 4-aminoquinolines, as a reversible inhibitor of the gastric (H+ + K+)-ATPase. This compound has been studied in gastric membrane vesicle preparations enriched in the (H+ + K+)-ATPase. At pH 7.0, SK&F 96067 inhibited K(+)-stimulated ATPase activity competitively with respect to the activating cation K+, with a Ki value of 0.39 +/- 0.05 microM. Under comparable conditions, SK&F 96067 was 32 times more potent as an inhibitor of the gastric (H+ + K+)-ATPase relative to the closely related (Na+ + K+)-ATPase. Studies in intact gastric vesicles showed that SK&F 96067 also inhibited hydrogen ion transport. Using the initial rate of acridine orange quenching as the index of acidification, an IC50 of 0.84 +/- 0.24 microM was observed. Steady state acidification, as measured by aminopyrine accumulation, was inhibited with greater potency (IC50 = 0.06 +/- 0.01 microM) consistent with the accumulation of this inhibitor into the intravesicular acidic space to a site of action on the inside (lumenal) face of the enzyme. Inhibition of ATPase activity in the presence of both SK&F 96067 and the K(+)-competitive (H+ + K+)-ATPase inhibitor, SCH 28080, indicated that their binding was mutually exclusive, consistent with SK&F 96067 acting at the same lumenal binding site as does SCH 28080. The steady-state inhibition kinetics of SK&F 96067 against K(+)-stimulated ATPase activity were followed as a function of pH. At pH 6.6 and 7.0 the inhibition was competitive with respect to the activating cation K+. At pH 7.5 and 8.1 a mixed pattern of inhibition was detected. Thus, at alkaline pH values, the binding of SK&F 96067 and K+ were no longer mutually exclusive. The potency of SK&F 96067 decreased as pH rose, consistent with the protonated form of the inhibitor being the preferred inhibitory species. A kinetic model is discussed, in which, at acidic pH, the protonated form of SK&F 96067 binds to the enzyme competitively with respect to K+, whereas, at alkaline pH, the neutral form of SK&F 96067 can bind simultaneously with K+.

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Indication	Highest Phase	Country/Location	Organization	Date
Gastrointestinal Diseases	Preclinical	GB	Smithkline Beecham Pharmaceuticals Ltd.	01 May 2002
Peptic Ulcer	Preclinical	US	-	-
Stomach Ulcer	Preclinical	-	GSK Plc	-

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