Optimization of 1,3,4-benzotriazepine-based CCK(2) antagonists to obtain potent, orally active inhibitors of gastrin-mediated gastric acid secretion.
Starting from a novel, achiral 1,3,4-benzotriazepine-based CCK2 receptor antagonist, a process of optimization has afforded further compounds of this type that maintain the nanomolar affinity for recombinant, human CCK2 receptors and high selectivity over CCK1 receptors observed in the initial lead but display more potent inhibition of pentagastrin-stimulated gastric acid secretion in vivo. Moreover, this has largely been achieved without altering their potency at wild-type canine and rat receptors, as judged by their displacement of [125I]-BH-CCK-8S in a radioligand binding assay and by their activity in an isolated, perfused rat stomach bioassay, respectively. 2-(5-Cyclohexyl-1-(2-cyclopentyl-2-oxo-ethyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl)-N-(3-(5-oxo-2,5-dihydro- [1,2,4]oxadiazol-3-yl)-phenyl)-acetamide (47) was identified as the most effective compound stemming from this approach, proving to be a potent inhibitor of pentagastrin-stimulated gastric acid secretion in rats and dogs by intravenous bolus as well as by enteral administration.
McDonald
Iain M
IM
James Black Foundation, 68 Half Moon Lane, Dulwich, London, SE24 9JE, United Kingdom. iain.mcdonald@kcl.ac.uk
Black
James W
JW
Buck
Ildiko M
IM
Dunstone
David J
DJ
Griffin
Eric P
EP
Harper
Elaine A
EA
Hull
Robert A D
RA
Kalindjian
S Barret
SB
Lilley
Elliot J
EJ
Linney
Ian D
ID
Pether
Michael J
MJ
Roberts
Sonia P
SP
Shaxted
Mark E
ME
Spencer
John
J
Steel
Katherine I M
KI
Sykes
David A
DA
Walker
Martin K
MK
Watt
Gillian F
GF
Wright
Laurence
L
Wright
Paul T
PT
Xun
Wei
W
D000284:Administration, Oral; D000818:Animals; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004285:Dogs; D005744:Gastric Acid / Q000378:metabolism*; D005753:Gastric Mucosa / Q000378:metabolism; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D051379:Mice; D041681:NIH 3T3 Cells; D010418:Pentagastrin / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D043887:Receptor, Cholecystokinin B / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
C531041:2-(5-cyclohexyl-1-(2-cyclopentyl-2-oxoethyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl)-N-(3-(5-oxo-2,5-dihydro-(1,2,4)oxadiazol-3-yl)phenyl)acetamide; D043887:Receptor, Cholecystokinin B; D011994:Recombinant Proteins; D001569:Benzodiazepines; D010418:Pentagastrin