Methods for drug discovery: development of potent, selective, orally effective cholecystokinin antagonists.
3-(Acylamino)-5-phenyl-2H-1,4-benzodiazepines, antagonists of the peptide hormone cholecystokinin (CCK), are described. Developed by reasoned modification of the known anxiolytic benzodiazepines, these compounds provide highly potent, orally effective ligands selective for peripheral (CCK-A) receptors, with binding affinities approaching or equaling that of the natural ligand CCK-8. The distinction between CCK-A receptors on the one hand and CNS (CCK-B), gastrin, and central benzodiazepine receptors on the other is demonstrated by using the structure-activity profiles of the new compounds. Details of the binding of these agents to CCK-A receptors are examined, and the method of development of these compounds is discussed in terms of its relevance to the general problem of drug discovery.
Evans
B E
BE
Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania 19486.
Rittle
K E
KE
Bock
M G
MG
DiPardo
R M
RM
Freidinger
R M
RM
Whitter
W L
WL
Lundell
G F
GF
Veber
D F
DF
Anderson
P S
PS
Chang
R S
RS
D000284:Administration, Oral; D000818:Animals; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D002766:Cholecystokinin / Q000037:antagonists & inhibitors*; D015195:Drug Design; D051379:Mice; D011949:Receptors, Cholecystokinin / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism; D013329:Structure-Activity Relationship
D011949:Receptors, Cholecystokinin; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D002766:Cholecystokinin