Synthesis of (aryloxy)alkylamines. 1. Novel antisecretory agents with H+K+-ATPase inhibitory activity.
A series of heterocyclic (aryloxy)alkylamines of structures II and III were prepared and found to possess gastric antisecretory activity. Of the variety of substituted thiazoles, benzoxazoles, and benzothiazoles prepared, thiazole 18, benzoxazole 32, and benzothiazole 47 exhibited gastric antisecretory potency comparable to that of ranitidine in vivo in the pylorous ligated rat model. In an isolated rabbit parietal system, the series of thiazoles, benzoxazoles, and benzothiazoles also demonstrated similar potency to that of ranitidine toward the inhibition of both histamine-stimulated and dcAMP-stimulated uptake of amino[14C]pyrine. These compounds inhibited the H+K+-sensitive ATPase enzyme in isolated gastric microsomes. A direct correlation existed between inhibition of 14C uptake, in vivo antisecretory activity, and inhibition of the H+K+-ATPase enzyme. The more potent antisecretory compounds 18, 32, and 47 were also the more potent enzyme inhibitors. These data suggest that the mechanism responsible for the observed in vitro and in vivo gastric antisecretory activity, in these series of compounds, is a consequence of the inhibition of the H+K+-sensitive ATPase enzyme.
Sanfilippo
P J
PJ
Research Laboratories, Ortho Pharmaceutical Corporation, Raritan, New Jersey 08869.
Urbanski
M
M
Press
J B
JB
Hajos
Z G
ZG
Shriver
D A
DA
Scott
C K
CK
D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors*; D000588:Amines / Q000138:chemical synthesis* / Q000494:pharmacology; D000632:Aminopyrine / Q000378:metabolism; D000818:Animals; D052160:Benzothiazoles; D001583:Benzoxazoles / Q000138:chemical synthesis / Q000494:pharmacology; D003994:Bucladesine / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D002927:Cimetidine / Q000494:pharmacology; D005744:Gastric Acid / Q000378:metabolism*; D005753:Gastric Mucosa / Q000187:drug effects; D017506:H(+)-K(+)-Exchanging ATPase; D006632:Histamine / Q000494:pharmacology; D008026:Ligation; D008297:Male; D009853:Omeprazole / Q000494:pharmacology; D010295:Parietal Cells, Gastric / Q000187:drug effects / Q000378:metabolism; D011706:Pyloric Antrum / Q000502:physiology; D011899:Ranitidine / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000494:pharmacology
D000588:Amines; D052160:Benzothiazoles; D001583:Benzoxazoles; D013844:Thiazoles; D000632:Aminopyrine; D003994:Bucladesine; D002927:Cimetidine; D006632:Histamine; D011899:Ranitidine; D000251:Adenosine Triphosphatases; D017506:H(+)-K(+)-Exchanging ATPase; C005465:benzothiazole; D009853:Omeprazole