Synthesis and SAR of new 5-phenyl-3-ureido-1,5-benzodiazepines as cholecystokinin-B receptor antagonists.
A series of 5-phenyl-3-ureidobenzodiazepine-2,4-diones was synthesized and evaluated as cholecystokinin-B (CCK-B) receptor antagonists. Structure-activity relationship (SAR) studies revealed the importance of the N-1 substituent for potent and selective CCK-B affinity. Addition of substituents at the urea side chain provided in some cases more potent compounds. Moreover the introduction of bulky substituents such as adamantylmethyl at N-1 and resolution of the racemic ureas resulted in our lead compound GV150013.
Ursini
A
A
Glaxo Wellcome Medicines Research Centre, Via A. Fleming 4, 37135 Verona, Italy. au4438@glaxowellcome.co.uk
Capelli
A M
AM
Carr
R A
RA
Cassarà
P
P
Corsi
M
M
Curcuruto
O
O
Curotto
G
G
Dal Cin
M
M
Davalli
S
S
Donati
D
D
Feriani
A
A
Finch
H
H
Finizia
G
G
Gaviraghi
G
G
Marien
M
M
Pentassuglia
G
G
Polinelli
S
S
Ratti
E
E
Reggiani
A M
AM
Tarzia
G
G
Tedesco
G
G
Tranquillini
M E
ME
Trist
D G
DG
Van Amsterdam
F T
FT
Reggiani
A
A
D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002144:Callithrix; D002540:Cerebral Cortex / Q000378:metabolism; D018360:Crystallography, X-Ray; D006168:Guinea Pigs; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D008566:Membranes; D051379:Mice; D008958:Models, Molecular; D010179:Pancreas / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D043886:Receptor, Cholecystokinin A; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D014151:Anti-Anxiety Agents; D043886:Receptor, Cholecystokinin A; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; D001569:Benzodiazepines