title: 5-(Piperidin-2-yl)- and 5-(homopiperidin-2-yl)-1,4-benzodiazepines: high-affinity, basic ligands for the cholecystokinin-B receptor.
abstract: 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).
authors.affiliation: Chemistry Department, Merck Sharp & Dohme Research Laboratories, Harlow, Essex, U.K.
authors.forename: J L
authors.initials: JL
authors.lastname: Castro
authors.forename: H B
authors.initials: HB
authors.lastname: Broughton
authors.forename: M G
authors.initials: MG
authors.lastname: Russell
authors.forename: D
authors.initials: D
authors.lastname: Rathbone
authors.forename: A P
authors.initials: AP
authors.lastname: Watt
authors.forename: R G
authors.initials: RG
authors.lastname: Ball
authors.forename: K L
authors.initials: KL
authors.lastname: Chapman
authors.forename: S
authors.initials: S
authors.lastname: Patel
authors.forename: A J
authors.initials: AJ
authors.lastname: Smith
authors.forename: G R
authors.initials: GR
authors.lastname: Marshall
authors.forename: V G
authors.initials: VG
authors.lastname: Matassa
mesh_terms: 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
chemical_list: 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