REVERSIBLE INHIBITORS OF THE GASTRIC (H+ K+)-ATPASE .4. IDENTIFICATION OF AN INHIBITOR WITH AN INTERMEDIATE DURATION OF ACTION/

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 structur e-activity relationship of this series is developed. Only a limited ra nge of substituents are tolerated on the N-aryl ring or the 6- and 7-p ositions of the quinoline, and although hydroxylated derivatives were identified possessing markedly greater affinity for the enzyme, none o f these proved to have adequate potency after oral dosing. In contrast , the 8-position of the quinoline ring proved suitable for a wide vari ety of substituents, allowing modification of physicochemical properti es while retaining primary activity. This led to the identification of compound 4 (SK&F 97574), which combines good oral potency with a some what longer duration of action than 3 (though much shorter than covale nt inhibitors such as omeprazole). This compound was selected for furt her development and evaluation in man.