5-(Piperidin-2-yl)- and 5-(homopiperidin-2-yl)-1,4-benzodiazepines: high-affinity, basic ligands for the cholecystokinin-B receptor.
The design, synthesis, and biological activity of a series of high-affinity, basic ligands for the cholecystokinin-B receptor are described. The compounds, which incorporate a piperidin-2-yl or a homopiperidin-2-yl group attached to C5 of a benzodiazepine core structure, are substantially more basic (e.g., 9d, pKa = 9.48) than previously reported antagonists based on 5-amino-1,4-benzodiazepines (e.g., 5, pKa = 7.1) and have improved aqueous solubility. In view of their basicity, it would be tempting to speculate that the present series of compounds might be binding to the CCK-B receptor in their protonated form. Compounds such as 9d, e and 10d showed high affinity for this receptor (IC50 < 2.5 nM) and very good selectivity over CCK-A (CCK-A/CCK-B > 2000), even as the racemates. Additionally, a significantly improved in vivo half-life was observed for a selection of compounds compared to the clinical candidate L-365, -260 (1).
Castro
J L
JL
Chemistry Department, Merck Sharp & Dohme Research Laboratories, Harlow, Essex, U.K.
Broughton
H B
HB
Russell
M G
MG
Rathbone
D
D
Watt
A P
AP
Ball
R G
RG
Chapman
K L
KL
Patel
S
S
Smith
A J
AJ
Marshall
G R
GR
Matassa
V G
VG
D000818:Animals; D001569:Benzodiazepines / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology; D001570:Benzodiazepinones / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D006168:Guinea Pigs; D008024:Ligands; D008958:Models, Molecular; D010671:Phenylurea Compounds; D010880:Piperidines / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D043886:Receptor, Cholecystokinin A; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013329:Structure-Activity Relationship
D001570:Benzodiazepinones; D008024:Ligands; D010671:Phenylurea Compounds; D010880:Piperidines; D043886:Receptor, Cholecystokinin A; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; D001569:Benzodiazepines; C058121:L 365260