SK&F 97574 (3-butyryl-4-(2-methylamino)-8-(2-hydroxyethoxy)quinoline), is a potent inhibitor of the (H+/K+)-ATPase in membrane vesicles isolated from porcine gastric mucosa. It inhibits (H+/K+)-ATPase activity in lyophilised vesicles in a kinetically competitive manner with respect to the activating cation, K+, with an inhibition constant (Ki) of 0.46 +/- 0.003 microM. Inhibition of (H+/K+)-ATPase activity is freely reversible. Binding of SK&F 97574 was shown to be mutually exclusive and the previously reported reversible (H+/K+)-ATPase inhibitors, SCH 28080 and MDPQ. Therefore, despite its structural dissimilarity, SK&F 97574 appears to bind to the same lumenal region of the (H+/K+)-ATPase identified as the binding site for these compounds. SK&F 97574 is a weak base (pKa = 6.86), and would therefore be expected to accumulate in the acidic compartment at the lumenal face of the parietal cell. In intact gastric vesicles (which have the lumenal face of the ATPase on the interior), SK&F 97574 inhibited ATP-dependent H(+)-transport with a similar potency to ATPase activity. SK&F 97574 is therefore relatively membrane permeable, and would be predicted to gain access readily to its site of action in vivo. The effect of pH on inhibition of H+/K(+)-ATPase activity by SK&F 97574 is consistent with its being active only in its protonated form. The selectivity of SK&F 97574 for the gastric (H+/K+)-ATPase was tested by examining its ability to inhibit a closely related p-class pump, the (Na+/K+)-ATPase from dog kidney. SK&F 97574 was found to have a 60-fold greater sensitivity for the former enzyme. The (Na+/K+)-ATPase was not inhibited in a K(+)-competitive manner by SK&F 97574, indicating an entirely different, probably nonspecific, mechanism.

1995-11-01·Biochemical pharmacology2区 · 医学

properties of the reversible, K+-competitive inhibitor of the gastric H+/K+)-ATPase, SK&F 97574. II. Pharmacological properties

2区 · 医学

Article

作者: Parsons, Michael E. ; Rasmussen, Tony C. ; Rushant, Beverly ; Postius, Stefan ; Leach, Colin ; Pope, Andrew J. ; Ife, Robert J.

SK&F 97574 [3-Butryl-4-(2-methylamino)-8-(2-hydroxyethoxy) quinoline] is a potent, reversible inhibitor of the gastric (H+/K+)-ATPase. In an anaesthetised lumen-perfused rat preparation, it inhibited pentagastrin-stimulated gastric acid secretion with intravenous and intraduodenal inhibitory ED50 values of 2.40 mumol/kg and 4.43 mumol/kg, respectively. In the conscious fistula rat model, doses of 10 mumol/kg IV and 25 mumol/kg PO produced mean peak inhibitions of basal acid output of 91% and 97%, respectively. In these experiments, the duration of action of SK&F 97574 was much shorter than that of the covalent (H+/K+)-ATPase inhibitor, omeprazole. In the conscious Heidenhain pouch dog, SK&F 97574 inhibited histamine-stimulated gastric acid secretion after both intravenous and oral administration with ED50 values of 0.49 mumol/kg and 0.89 mumol/kg, respectively. In this model, duration of action studies showed that significant residual inhibition of acid secretion remained 8 hours after intravenous dosing with SK&F 97574 (producing peak inhibition of 92%). However, 24 hours after oral dosing of SK&F 97574 (10 mumol/kg), no significant inhibition remained. These data indicate that the duration of action of SK&F 97574 is longer than that of the histamine H2 receptor antagonists such as cimetidine, but shorter than that of covalent (H+/K+)-inhibitors such as omeprazole. Overall, the pharmacological properties of SK&F 97574 suggest that it could be a potentially useful clinical treatment for acid-related diseases.

1995-07-01·Journal of medicinal chemistry1区 · 医学

Reversible Inhibitors of the Gastric (H+/K+)-ATPase. 4. Identification of an Inhibitor with an Intermediate Duration of Action

1区 · 医学

Article

作者: Parsons, Michael E. ; Ife, Robert J. ; Keeling, David J. ; Theobald, Colin J. ; Leach, Colin A. ; Brown, Thomas H. ; Wiggall, Kenneth J.

3-Acyl-4-(arylamino)quinolines were previously identified as gastric (H+/K+)-ATPase inhibitors, and clinical efficacy has been demonstrated for compound 3 (SK&F 96067). In the present study the further structure-activity relationship of this series is developed. Only a limited range of substituents are tolerated on the N-aryl ring or the 6- and 7-positions of the quinoline, and although hydroxylated derivatives were identified possessing markedly greater affinity for the enzyme, none of these proved to have adequate potency after oral dosing. In contrast, the 8-position of the quinoline ring proved suitable for a wide variety of substituents, allowing modification of physicochemical properties while retaining primary activity. This led to the identification of compound 4 (SK&F 97574), which combines good oral potency with a somewhat longer duration of action than 3 (though much shorter than covalent inhibitors such as omeprazole). This compound was selected for further development and evaluation in man.

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