2,7-Dioxo-2,3,4,5,6,7-hexahydro-1H-benzo[h][1,4]diazonine as a new template for the design of CCK(2) receptor antagonists.
A novel series of nonpeptide CCK(2) receptor antagonists has been prepared, in which 2,7-dioxo-2,3,4,5,6,7-hexahydro-1H-benzo[h][1, 4]diazonine (5) was used as a chemical template. This uncommon ring system was obtained in a highly substituted form and in high yield by ozonolysis of the enamine bond of 1,2,3,4-tetrahydro-9H-pyrido[3, 4-b]indole derivatives (4), in which the configuration of the substituents was established stereoselectively via the Pictet-Spengler reaction. Further structural manipulation was guided by molecular modeling through comparison of fieldpoint-based structures of candidate compounds with a selected low-energy conformation of the representative CCK(2) receptor antagonist 5-[[[(1S)-[[(3, 5-dicarboxyphenyl)amino]carbonyl]-2-phenylethyl]amino]carbonyl]-6- [[( 1-adamantylmethyl)amino]carbonyl]indole (JB93182 (3)). By this approach compounds such as (3R, 5S)-4-acetyl-3-(1-adamantyl)methyl-1-(2-chlorobenzyl)-5-carboxymet hyl aminocarbonyl-2,7-dioxo-2,3,4,5,6,7-hexahydro-1H-benzo[h][1, 4]diazonine (32) were prepared. Compound 32 behaved as a competitive CCK(2) receptor antagonist in vitro as judged by its inhibition of pentagastrin-stimulated acid secretion in an isolated, lumen-perfused, immature rat stomach assay (pK(B) = 6.74 +/- 0.27) and by its displacement of [(125)I]CCK-8S from CCK(2) sites in mouse cortical homogenates (pK(i) = 6.99 +/- 0.05). Compound 32 was 100-fold selective for CCK(2) over CCK(1) receptors based on the affinity estimate obtained in a guinea pig pancreas radioligand binding assay (pK(i) = 5.0).
McDonald
I M
IM
James Black Foundation, 68 Half Moon Lane, Dulwich, London SE24 9JE, U.K. iain.mcdonald@kcl.ac.uk
Dunstone
D J
DJ
Kalindjian
S B
SB
Linney
I D
ID
Low
C M
CM
Pether
M J
MJ
Steel
K I
KI
Tozer
M J
MJ
Vinter
J G
JG
D000818:Animals; D001667:Binding, Competitive; D015195:Drug Design; D005744:Gastric Acid / Q000378:metabolism; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008958:Models, Molecular; D010179:Pancreas / Q000378:metabolism; D011809:Quinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C414213:2,7-dioxo-2,3,4,5,6,7-hexahydro-1H-benzo(h)(1,4)diazonine; D011809:Quinones; D011949:Receptors, Cholecystokinin