Cholecystokinin antagonists. Synthesis and biological evaluation of 4-substituted 4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepines.
A series of 4-substituted 4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepines was prepared by standard methodology. These compounds were tested in vitro as antagonists of the binding of [125I]cholecystokinin (CCK) to rat pancreas and guinea pig brain receptors and of the binding of [125I]gastrin to guinea pig gastric glands. All compounds proved to have greater affinity for the peripheral CCK receptor with some analogues having IC50's in the subnanomolar range. In vivo activity of selected compounds in mice is presented and the structure/activity profile of this class of benzodiazepines as CCK antagonists is discussed.
Bock
M G
MG
Department of Medicinal Chemistry, Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania 19486.
DiPardo
R M
RM
Evans
B E
BE
Rittle
K E
KE
Veber
D F
DF
Freidinger
R M
RM
Chang
R S
RS
Lotti
V J
VJ
D000818:Animals; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D002766:Cholecystokinin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005746:Gastric Emptying / Q000187:drug effects; D005753:Gastric Mucosa / Q000378:metabolism; D006168:Guinea Pigs; D007202:Indicators and Reagents; D010179:Pancreas / Q000378:metabolism; D051381:Rats; D011949:Receptors, Cholecystokinin / Q000187:drug effects / Q000378:metabolism; D012844:Sincalide / Q000037:antagonists & inhibitors / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000494:pharmacology
D007202:Indicators and Reagents; D011949:Receptors, Cholecystokinin; D014230:Triazoles; D001569:Benzodiazepines; D002766:Cholecystokinin; D012844:Sincalide