The cholecystokinin CCK2 receptor antagonist, JNJ-26070109, inhibits gastric acid secretion and prevents omeprazole-induced acid rebound in the rat.
OBJECTIVE
JNJ-26070109 [(R)4-bromo-N-[1-(2,4-difluoro-phenyl)-ethyl]-2-(quinoxaline-5-sulfonylamino)-benzamide] is a novel antagonist at cholecystokinin CCK(2) receptors with good pharmacokinetic properties and represents a novel mechanism for the treatment of gastro-oesophageal reflux disease (GORD). The purpose of the present study was to determine whether chronic treatment with JNJ-26070109 could prevent, as well as treat, acid rebound in rats.


METHODS
A chronic fistula was surgically inserted into the stomach of rats to enable the measurement of acid secretion under basal, pentagastrin and histamine-stimulated conditions. JNJ-26070109 and omeprazole were administered separately and in combination.


RESULTS
Sustained administration of omeprazole alone and in combination with JNJ-26070109 inhibited gastric acid secretion by >90%. However, 3 days after withdrawing treatment, there was a rebound hypersecretion by ∼1.5-fold in omeprazole-treated animals. No such acid rebound was observed with JNJ-26070109 alone or with co-administration of JNJ-26070109 and omeprazole. The anti-trophic effects of JNJ-26070109 in the gastric mucosal paralleled the effects on acid rebound. Administration of JNJ-26070109 for 3 days after cessation of omeprazole prevented the occurrence of acid rebound. Interestingly, chronic, but not acute, treatment with JNJ-26070109 also inhibited histamine-stimulated acid secretion.


CONCLUSIONS
Chronic administration of JNJ-26070109 effectively inhibited gastric acid secretion and suppressed proton pump inhibitor (PPI)-induced acid rebound in the rat. This work advances the field by demonstrating that modest doses of a competitive CCK(2) receptor antagonist have significant and functionally important anti-trophic actions in the gastric mucosa. These properties make JNJ-26070109 a suitable candidate for clinical investigation for the treatment of GORD.
Cardiovascular Metabolic Research, Janssen Pharmaceutical Companies of Johnson & Johnson, San Diego, CA, USA. tbarret1@its.jnj.com
T D
TD
Barrett
G
G
Lagaud
P
P
Wagaman
J M
JM
Freedman
W
W
Yan
L
L
Andries
M C
MC
Rizzolio
M F
MF
Morton
N P
NP
Shankley
D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology; D005744:Gastric Acid / Q000378:metabolism*; D005755:Gastrins / Q000097:blood; D006632:Histamine; D008297:Male; D009853:Omeprazole / Q000494:pharmacology; D010418:Pentagastrin; D011810:Quinoxalines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043887:Receptor, Cholecystokinin B / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000494:pharmacology*
C560626:4-bromo-N-(1-(2,4-difluoro-phenyl)ethyl)-2-(quinoxaline-5-sulfonylamino)benzamide; D000897:Anti-Ulcer Agents; D005755:Gastrins; D011810:Quinoxalines; D043887:Receptor, Cholecystokinin B; D013449:Sulfonamides; D006632:Histamine; D010418:Pentagastrin; D009853:Omeprazole