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.
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.
Buck
Ildiko M
IM
James Black Foundation, 68 Half Moon Lane, London SE24 9JE, U.K. ildiko.buck@kcl.ac.uk
Black
James W
JW
Cooke
Tracey
T
Dunstone
David J
DJ
Gaffen
John D
JD
Griffin
Eric P
EP
Harper
Elaine A
EA
Hull
Robert A D
RA
Kalindjian
S Barret
SB
Lilley
Elliot J
EJ
Linney
Ian D
ID
Low
Caroline M R
CM
McDonald
Iain M
IM
Pether
Michael J
MJ
Roberts
Sonia P
SP
Shankley
Nigel P
NP
Shaxted
Mark E
ME
Steel
Katherine I M
KI
Sykes
David A
DA
Tozer
Matthew J
MJ
Watt
Gillian F
GF
Walker
Martin K
MK
Wright
Laurence
L
Wright
Paul T
PT
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*
D007093:Imidazoles; D011758:Pyrroles; D043887:Receptor, Cholecystokinin B; D010418:Pentagastrin