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 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.
Leach
C A
CA
SmithKline Beecham Pharmaceuticals R&D, The Frythe, Welwyn, Herts, England.
Brown
T H
TH
Ife
R J
RJ
Keeling
D J
DJ
Parsons
M E
ME
Theobald
C J
CJ
Wiggall
K J
KJ
D009682:Magnetic Resonance Spectroscopy; D054328:Proton Pump Inhibitors; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D013270:Stomach / Q000201:enzymology*; D013329:Structure-Activity Relationship; D013997:Time Factors
D054328:Proton Pump Inhibitors; D011804:Quinolines