title: Optimization of 1,3,4-benzotriazepine-based CCK(2) antagonists to obtain potent, orally active inhibitors of gastrin-mediated gastric acid secretion.
abstract: Starting from a novel, achiral 1,3,4-benzotriazepine-based CCK2 receptor antagonist, a process of optimization has afforded further compounds of this type that maintain the nanomolar affinity for recombinant, human CCK2 receptors and high selectivity over CCK1 receptors observed in the initial lead but display more potent inhibition of pentagastrin-stimulated gastric acid secretion in vivo. Moreover, this has largely been achieved without altering their potency at wild-type canine and rat receptors, as judged by their displacement of [125I]-BH-CCK-8S in a radioligand binding assay and by their activity in an isolated, perfused rat stomach bioassay, respectively. 2-(5-Cyclohexyl-1-(2-cyclopentyl-2-oxo-ethyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl)-N-(3-(5-oxo-2,5-dihydro- [1,2,4]oxadiazol-3-yl)-phenyl)-acetamide (47) was identified as the most effective compound stemming from this approach, proving to be a potent inhibitor of pentagastrin-stimulated gastric acid secretion in rats and dogs by intravenous bolus as well as by enteral administration.
authors.affiliation: James Black Foundation, 68 Half Moon Lane, Dulwich, London, SE24 9JE, United Kingdom. iain.mcdonald@kcl.ac.uk
authors.forename: Iain M
authors.initials: IM
authors.lastname: McDonald
authors.forename: James W
authors.initials: JW
authors.lastname: Black
authors.forename: Ildiko M
authors.initials: IM
authors.lastname: Buck
authors.forename: David J
authors.initials: DJ
authors.lastname: Dunstone
authors.forename: Eric P
authors.initials: EP
authors.lastname: Griffin
authors.forename: Elaine A
authors.initials: EA
authors.lastname: Harper
authors.forename: Robert A D
authors.initials: RA
authors.lastname: Hull
authors.forename: S Barret
authors.initials: SB
authors.lastname: Kalindjian
authors.forename: Elliot J
authors.initials: EJ
authors.lastname: Lilley
authors.forename: Ian D
authors.initials: ID
authors.lastname: Linney
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Pether
authors.forename: Sonia P
authors.initials: SP
authors.lastname: Roberts
authors.forename: Mark E
authors.initials: ME
authors.lastname: Shaxted
authors.forename: John
authors.initials: J
authors.lastname: Spencer
authors.forename: Katherine I M
authors.initials: KI
authors.lastname: Steel
authors.forename: David A
authors.initials: DA
authors.lastname: Sykes
authors.forename: Martin K
authors.initials: MK
authors.lastname: Walker
authors.forename: Gillian F
authors.initials: GF
authors.lastname: Watt
authors.forename: Laurence
authors.initials: L
authors.lastname: Wright
authors.forename: Paul T
authors.initials: PT
authors.lastname: Wright
authors.forename: Wei
authors.initials: W
authors.lastname: Xun
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004285:Dogs; D005744:Gastric Acid / Q000378:metabolism*; D005753:Gastric Mucosa / Q000378:metabolism; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D051379:Mice; D041681:NIH 3T3 Cells; D010418:Pentagastrin / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D043887:Receptor, Cholecystokinin B / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
chemical_list: C531041:2-(5-cyclohexyl-1-(2-cyclopentyl-2-oxoethyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl)-N-(3-(5-oxo-2,5-dihydro-(1,2,4)oxadiazol-3-yl)phenyl)acetamide; D043887:Receptor, Cholecystokinin B; D011994:Recombinant Proteins; D001569:Benzodiazepines; D010418:Pentagastrin