Non-peptide cholecystokinin-B/gastrin receptor antagonists based on bicyclic, heteroaromatic skeletons.
A series of potent and selective cholecystokinin-B/gastrin receptor antagonists based on the dibenzobicyclo[2.2.2]octane (BCO) skeleton which have recently been described were found to show species-dependent behavior when examined in rat and dog models. We now report the discovery of compounds in which the BCO skeleton has been replaced with bicyclic, heteroaromatic frameworks, such as a 5,6-disubstituted indole or benzimidazole. These new ligands maintain the affinity and selectivity profile of the previous compounds in vitro but show a much more consistent behavior pattern in vivo. Representative examples of this class of compound have been shown to inhibit pentagastrin-stimulated acid secretion when administered intravenously at doses of 0.1 mumol kg-1 or less.
Kalindjian
S B
SB
James Black Foundation, London, U.K.
Buck
I M
IM
Davies
J M
JM
Dunstone
D J
DJ
Hudson
M L
ML
Low
C M
CM
McDonald
I M
IM
Pether
M J
MJ
Steel
K I
KI
Tozer
M J
MJ
Vinter
J G
JG
D000818:Animals; D004285:Dogs; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D011083:Polycyclic Compounds / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*; D013045:Species Specificity
D011083:Polycyclic Compounds; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; C096271:dibenzobicyclo(2.2.2)octane