Reversible inhibitors of the gastric (H+/K+)-ATPase. 1. 1-Aryl-4-methylpyrrolo[3,2-c]quinolines as conformationally restrained analogues of 4-(arylamino)quinolines.
The 4-(arylamino)quinoline 4, previously described as an antiulcer compound, is shown to be an inhibitor of the gastric (H+/K+)-ATPase. It is postulated that 1-arylpyrrolo[3,2-c]quinolines 6 act as conformationally restrained analogues of 4. A series of derivatives of 6 has been prepared and shown to be potent inhibitors of the target enzyme in vitro. Substitution in the ortho position of the aryl ring is important for activity. Unsaturation in the 5-membered ring makes little difference, but introduction of heteroatoms into the same ring markedly reduces activity. In more detailed kinetic experiments, 15c and 4 both show reversible, K(+)-competitive binding to the enzyme, with submicromolar Ki values. The compounds appear to act at the lumenal face of the enzyme and to require protonation for activity. Several compounds in the series are shown to be potent inhibitors of pentagastrin-stimulated acid secretion in the rat.
Brown
T H
TH
Department of Medicinal Chemistry, Smith Kline & French Research Ltd., Welwyn, Herts, England.
Ife
R J
RJ
Keeling
D J
DJ
Laing
S M
SM
Leach
C A
CA
Parsons
M E
ME
Price
C A
CA
Reavill
D R
DR
Wiggall
K J
KJ
D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors*; D000634:Aminoquinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D005750:Gastric Juice / Q000378:metabolism*; D005753:Gastric Mucosa / Q000201:enzymology*; D017506:H(+)-K(+)-Exchanging ATPase; D066298:In Vitro Techniques; D009038:Motion; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D012636:Secretory Rate / Q000187:drug effects; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship; D013552:Swine
D000634:Aminoquinolines; D004791:Enzyme Inhibitors; D011758:Pyrroles; D011804:Quinolines; D000251:Adenosine Triphosphatases; D017506:H(+)-K(+)-Exchanging ATPase