title: Discovery of 1,5-benzodiazepines with peripheral cholecystokinin (CCK-A) receptor agonist activity (II): Optimization of the C3 amino substituent.
abstract: Analogs of the previously reported 1,5-benzodiazepine peripheral cholecystokinin (CCK-A) receptor agonist 1 were prepared which explore substitution and/or replacement of the C-3 phenyl urea moiety. Agonist efficacy on the isolated guinea pig gallbladder (GPGB) was retained with a variety of substituted ureas and amide analogs. Three compounds were identified which were orally active in the mouse gallbladder emptying assay (MGBE). The 2-indolamide (52) and N-(carboxymethyl)-2-indolamide (54) derivatives had improved affinity for the human CCK-A receptor but reduced agonist efficacy on the GPGB. Neither indolamide was orally active in a rat feeding assay. In contrast, the (3-carboxyphenyl)urea derivative (29, GW7854) had moderately increased affinity for the human CCK-B receptor but was a potent full agonist on the GPGB and was orally active in both the MGBE and rat feeding assays. GW7854 was a full agonist (EC50 = 60 nM) for calcium mobilization on CHO K1 cells expressing hCCK-A receptors and a potent antagonist of CCK-8 (pA2 = 9.1) on CHO K1 cells expressing hCCK-B receptors. GW7854 is a potent mixed CCK-A agonist/CCK-B antagonist which is orally active in two in vivo models of CCK-A-mediated agonist activity.
authors.affiliation: Department of Medicinal Chemistry, Glaxo Wellcome Research and Development, Research Triangle Park, North Carolina 27709, USA.
authors.forename: G C
authors.initials: GC
authors.lastname: Hirst
authors.forename: C
authors.initials: C
authors.lastname: Aquino
authors.forename: L
authors.initials: L
authors.lastname: Birkemo
authors.forename: D K
authors.initials: DK
authors.lastname: Croom
authors.forename: M
authors.initials: M
authors.lastname: Dezube
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: B
authors.initials: B
authors.lastname: Henke
authors.forename: M K
authors.initials: MK
authors.lastname: James
authors.forename: M F
authors.initials: MF
authors.lastname: Johnson
authors.forename: T
authors.initials: T
authors.lastname: Momtahen
authors.forename: K L
authors.initials: KL
authors.lastname: Queen
authors.forename: R G
authors.initials: RG
authors.lastname: Sherrill
authors.forename: J
authors.initials: J
authors.lastname: Szewczyk
authors.forename: T M
authors.initials: TM
authors.lastname: Willson
authors.forename: E E
authors.initials: EE
authors.lastname: Sugg
mesh_terms: D000818:Animals; D001067:Appetite Depressants / Q000737:chemistry / Q000494:pharmacology*; D001569:Benzodiazepines / Q000737:chemistry / Q000494:pharmacology*; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D006224:Cricetinae; D005247:Feeding Behavior / Q000187:drug effects; D006168:Guinea Pigs; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D051381:Rats; D043886:Receptor, Cholecystokinin A; D011949:Receptors, Cholecystokinin / Q000819:agonists*; D016339:Spectrometry, Mass, Fast Atom Bombardment
chemical_list: D001067:Appetite Depressants; D043886:Receptor, Cholecystokinin A; D011949:Receptors, Cholecystokinin; D001569:Benzodiazepines; D002118:Calcium