title: Optimization of 3-(1H-indazol-3-ylmethyl)-1,5-benzodiazepines as potent, orally active CCK-A agonists.
abstract: We previously described a series of 3-(1H-indazol-3-ylmethyl)-1,5-benzodiazepine CCK-A agonists exemplified by compound 1 (GW 5823), which is the first reported binding selective CCK-A full agonist demonstrating oral efficacy in a rat feeding model. In this report we describe analogs of compound 1 designed to explore changes to the C3 and N1 pharmacophores and their effect on agonist activity and receptor selectivity. Agonist efficacy in this series was affected by stereoelectronic factors within the C3 moiety. Binding affinity for the CCK-A vs CCK-B receptor showed little dependence on the structure of the C3 moiety but was affected by the nature of the second substituent at C3. Structure-activity relationships at the N1-anilidoacetamide "trigger" moiety within the C3 indazole series were also investigated. Both agonist efficacy and binding affinity within this series were modulated by variation of substituents on the N1-anilidoacetamide moiety. Evaluation of several analogs in an vivo mouse gallbladder emptying assay revealed compound 1 to be the most potent and efficacious of all the analogs tested. The pharmacokinetic and pharmacodynamic profile of 1 in rats is also discussed.
authors.affiliation: Glaxo Wellcome Research and Development, Research Triangle Park, North Carolina 27709, USA. henke-br@glaxo.com
authors.forename: B R
authors.initials: BR
authors.lastname: Henke
authors.forename: C J
authors.initials: CJ
authors.lastname: Aquino
authors.forename: L S
authors.initials: LS
authors.lastname: Birkemo
authors.forename: D K
authors.initials: DK
authors.lastname: Croom
authors.forename: R W
authors.initials: RW
authors.lastname: Dougherty
authors.forename: G N
authors.initials: GN
authors.lastname: Ervin
authors.forename: M K
authors.initials: MK
authors.lastname: Grizzle
authors.forename: G C
authors.initials: GC
authors.lastname: Hirst
authors.forename: M K
authors.initials: MK
authors.lastname: James
authors.forename: M F
authors.initials: MF
authors.lastname: Johnson
authors.forename: K L
authors.initials: KL
authors.lastname: Queen
authors.forename: R G
authors.initials: RG
authors.lastname: Sherrill
authors.forename: E E
authors.initials: EE
authors.lastname: Sugg
authors.forename: E M
authors.initials: EM
authors.lastname: Suh
authors.forename: J W
authors.initials: JW
authors.lastname: Szewczyk
authors.forename: R J
authors.initials: RJ
authors.lastname: Unwalla
authors.forename: J
authors.initials: J
authors.lastname: Yingling
authors.forename: T M
authors.initials: TM
authors.lastname: Willson
mesh_terms: D000284:Administration, Oral; D000478:Alkylation; D000818:Animals; D001569:Benzodiazepines / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D001570:Benzodiazepinones / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D020109:Devazepide; D005704:Gallbladder / Q000187:drug effects / Q000378:metabolism; D006168:Guinea Pigs; D006727:Hormone Antagonists / Q000494:pharmacology; D007191:Indazoles / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D051379:Mice; D008956:Models, Chemical; D051381:Rats; D043886:Receptor, Cholecystokinin A; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin / Q000819:agonists* / Q000378:metabolism
chemical_list: D001570:Benzodiazepinones; D006727:Hormone Antagonists; D007191:Indazoles; D043886:Receptor, Cholecystokinin A; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; D001569:Benzodiazepines; D020109:Devazepide