McDonald I M, Dunstone D J, Kalindjian S B, Linney I D, Low C M, Pether M J, Steel K I, Tozer M J, Vinter J G
James Black Foundation, 68 Half Moon Lane, Dulwich, London SE24 9JE, U.K.
J Med Chem. 2000 Sep 21;43(19):3518-29. doi: 10.1021/jm000960w.
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).
已经制备了一系列新型非肽CCK(2)受体拮抗剂，其中2,7-二氧代-2,3,4,5,6,7-六氢-1H-苯并[h][1,4]二氮杂环辛烷(5)用作化学模板。通过对1,2,3,4-四氢-9H-吡啶并[3,4-b]吲哚衍生物(4)的烯胺键进行臭氧分解，以高取代形式和高收率获得了这种不常见的环系统，其中取代基的构型通过Pictet-Spengler反应立体选择性地确定。通过将候选化合物基于场点的结构与代表性CCK(2)受体拮抗剂5-[[[(1S)-[[(3,5-二羧基苯基)氨基]羰基]-2-苯乙基]氨基]羰基]-6-[[(1-金刚烷基甲基)氨基]羰基]吲哚(JB93182(3))的选定低能构象进行比较，分子建模指导了进一步的结构操作。通过这种方法制备了诸如(3R,5S)-4-乙酰基-3-(1-金刚烷基)甲基-1-(2-氯苄基)-5-羧甲基氨基羰基-2,7-二氧代-2,3,4,5,6,7-六氢-1H-苯并[h][1,4]二氮杂环辛烷(32)之类的化合物。在离体、腔灌注、未成熟大鼠胃试验中，通过其对五肽胃泌素刺激的胃酸分泌的抑制作用(pK(B)=6.74±0.27)以及通过其从小鼠皮质匀浆中的CCK(2)位点置换[(125)I]CCK-8S(pK(i)=6.99±0.05)判断，化合物32在体外表现为竞争性CCK(2)受体拮抗剂。基于在豚鼠胰腺放射性配体结合试验中获得的亲和力估计(pK(i)=5.0)，化合物32对CCK(2)受体的选择性比对CCK(1)受体高100倍。
