title: Optimization of the in vitro and in vivo properties of a novel series of 2,4,5-trisubstituted imidazoles as potent cholecystokinin-2 (CCK2) antagonists.
abstract: The systematic optimization of the structure of a novel 2,4,5-trisubstituted imidazole-based cholecystokinin-2 (CCK(2)) receptor antagonist afforded analogues with nanomolar receptor affinity. These compounds were now comparable in their potency to the bicyclic heteroaromatic-based compounds 5 (JB93182) and 6 (JB95008), from which the initial examples were designed using a field-point based molecular modeling approach. They were also orally active as judged by their inhibition of pentagastrin stimulated acid secretion in conscious dogs, in contrast to the bicyclic heteroaromatic-based compounds, which were ineffective because of biliary elimination. Increasing the hydrophilicity through replacement of a particular methylene group with an ether oxygen, as in 3-{[5-(adamantan-1-yloxymethyl)-2-cyclohexyl-1H-imidazole-4-carbonyl]amino}benzoic acid (53), had little effect on the receptor affinity but significantly increased the oral potency. Comparison of the plasma pharmacokinetics and the inhibition of pentagastrin-stimulated acid output following bolus intraduodenal administration of both 53 and 6 indicated that 53 was well absorbed, had a longer half-life, and was not subject to the elimination pathways of the earlier series.
authors.affiliation: James Black Foundation, 68 Half Moon Lane, London SE24 9JE, U.K. ildiko.buck@kcl.ac.uk
authors.forename: Ildiko M
authors.initials: IM
authors.lastname: Buck
authors.forename: James W
authors.initials: JW
authors.lastname: Black
authors.forename: Tracey
authors.initials: T
authors.lastname: Cooke
authors.forename: David J
authors.initials: DJ
authors.lastname: Dunstone
authors.forename: John D
authors.initials: JD
authors.lastname: Gaffen
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: Caroline M R
authors.initials: CM
authors.lastname: Low
authors.forename: Iain M
authors.initials: IM
authors.lastname: McDonald
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Pether
authors.forename: Sonia P
authors.initials: SP
authors.lastname: Roberts
authors.forename: Nigel P
authors.initials: NP
authors.lastname: Shankley
authors.forename: Mark E
authors.initials: ME
authors.lastname: Shaxted
authors.forename: Katherine I M
authors.initials: KI
authors.lastname: Steel
authors.forename: David A
authors.initials: DA
authors.lastname: Sykes
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Tozer
authors.forename: Gillian F
authors.initials: GF
authors.lastname: Watt
authors.forename: Martin K
authors.initials: MK
authors.lastname: Walker
authors.forename: Laurence
authors.initials: L
authors.lastname: Wright
authors.forename: Paul T
authors.initials: PT
authors.lastname: Wright
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002540:Cerebral Cortex / Q000378:metabolism; D004285:Dogs; D005260:Female; D005744:Gastric Acid / Q000378:metabolism; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D007262:Infusions, Intravenous; D051379:Mice; D008958:Models, Molecular; D010418:Pentagastrin / Q000008:administration & dosage / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D011869:Radioligand Assay; D043887:Receptor, Cholecystokinin B / Q000037:antagonists & inhibitors*
chemical_list: D007093:Imidazoles; D011758:Pyrroles; D043887:Receptor, Cholecystokinin B; D010418:Pentagastrin