5-Phenyl-3-ureidobenzazepin-2-ones as cholecystokinin-B receptor antagonists.
A series of 5-phenyl-3-ureidobenzazepin-2-one cholecystokinin-B (CCK-B) receptor antagonists was synthesized using Beckmann ring expansion of a suitable 4-phenyl-1-tetralone as a key step. Structure-activity relationship studies revealed the importance of the 5-phenyl group for potent and selective CCK-B affinity. Addition of an 8-methyl substituent and resolution provided the potent (CCK-B IC50 = 0.48 nM) CCK-B antagonist 4. The role of the 5-phenyl group as part of a "privileged structure" for high-affinity receptor antagonism is discussed.
Lowe
J A
JA
Central Research Division, Pfizer Inc., Groton, Connecticut 06340.
Hageman
D L
DL
Drozda
S E
SE
McLean
S
S
Bryce
D K
DK
Crawford
R T
RT
Zorn
S
S
Morrone
J
J
Bordner
J
J
D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D005744:Gastric Acid / Q000378:metabolism; D006168:Guinea Pigs; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D010418:Pentagastrin / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D001552:Benzazepines; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; D010418:Pentagastrin