REVERSIBLE INHIBITORS OF THE GASTRIC (H+/K+)-ATPASE .3. 3-SUBSTITUTED-4-(PHENYLAMINO)QUINOLINES

被引:51
作者
IFE, RJ
BROWN, TH
KEELING, DJ
LEACH, CA
MEESON, ML
PARSONS, ME
REAVILL, DR
THEOBALD, CJ
WIGGALL, KJ
机构
[1] SmithKline Beecham Pharmaceuticals R&D, Herts, AL6 9AR, Frythe, Welwyn
[2] Department of Cell Biology, Astra Hässle AB, S-431 83, Mölndal
关键词
D O I
10.1021/jm00096a018
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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 th bearing such a substituent, only a particular combination of properties provides high activity, both in as inhibitors of gastric acid secretion in vivo. The ability of the substituent to affect activity by restricting rotation about the C(quin)-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 oral dosing in the Heidenhain pouch dog and was selected for further development and evaluation in man.
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收藏
页码:3413 / 3422
页数:10
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