Reversible Inhibitors of the Gastric (H+/K+)-ATPase. 3. 3-substituted-4-(phenylamino)quinolines

J Med Chem. 1992 Sep 4;35(18):3413-22. doi: 10.1021/jm00096a018.

Abstract

Previously, gastric (H+/K+)-ATPase inhibitors such as 2 have been prepared as analogues of 1a on the presumption that the 3-carbethoxy substituent plays a key role in establishing the orientation of the 4-arylamino group. In this paper we explore further the contribution made to activity by the quinoline 3-substituent. We show that, for compounds bearing such a substituent, only a particular combination of properties provides high activity, both in vitro and as inhibitors of gastric acid secretion in vivo. The ability of the substituent to affect activity by restricting rotation about the Cquin-N bond through a combination of both a pi-electron withdrawal and hydrogen bonding is supported by the current study. However, high activity is only achieved if the effect of this group on the quinoline pK(a) is kept to a minimum. 3-Acyl substituents provide an optimum combination of electronic properties. From this series, compound 17c (SK&F 96067) was shown to be a potent inhibitor of histamine-stimulated gastric acid secretion after oral dosing in the Heidenhain pouch dog and was selected for further development and evaluation in man.

MeSH terms

  • Adenosine Triphosphatases / antagonists & inhibitors*
  • Animals
  • Dogs
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / pharmacology
  • Gastric Acid / metabolism
  • Gastric Mucosa / drug effects*
  • Gastric Mucosa / enzymology
  • H(+)-K(+)-Exchanging ATPase
  • Quinolines / pharmacology*
  • Rats
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Quinolines
  • Adenosine Triphosphatases
  • H(+)-K(+)-Exchanging ATPase