Fincham C I, Higginbottom M, Hill D R, Horwell D C, O'Toole J C, Ratcliffe G S, Rees D C, Roberts E
Parke-Davis Neuroscience Research Center, Addenbrookes Hospital Site, Cambridge, U.K.
J Med Chem. 1992 Apr 17;35(8):1472-84. doi: 10.1021/jm00086a017.
This paper describes the chemical synthesis and CCK-B and CCK-A receptor binding affinities of a series of compounds in which the central amide bond of the CCK-B "dipeptoid" ligand tricyclo[3.3.1.1(3,7)]dec-2-yl [R-(R*,S*)]-[2-[[1-(hydroxymethyl)- 2-phenylethyl]amino]-1-(1H-indol-3-ylmethyl)-2-oxoethyl]carb amate (4) (CCK-B IC50 = 852 nM), and tricyclo[3.3.1.1(3,7)]dec-2-yl (R)-[1-(1H-indol-3-ylmethyl)-1-methyl- 2-oxo-2-[(2-phenylethyl)amino]ethyl]carbamate (23) (CCK-B IC50 = 32 nM) is replaced by 11 different amide replacements. These replacements are the methyleneamino (CH2NH), the reverse amide (NHCO), the ester (COO), the N-methylamide (CONMe), the thioamide (CSNH), the N-acetylmethyleneamino (CH2NAc), the cis double bond (CHCH), the ethylene (CH2CH2), the thiolester (COS), the hydroxyethylene (CHOHCH2), and a 4,5-dihydro-1,3-thiazole. Most of the replacements have weaker affinity and reduced selectivity for the CCK-B receptor than the parent amide. However, this affinity can be improved by appending a fumarate side chain to the phenethyl group, e.g. tricyclo[3.3.1.1(3,7)]dec-2-yl-3-(1H-indol-3-yl-methyl)-3-methyl-4 ,9- dioxo-7-phenyl-5,13-dioxa-2,8-diazatetradec-10-enoate (36) (CCK-B IC50 = 38.8 nM). Replacement of the amide of compound 4 with a 4,5-dihydro-1,3-thiazole gives tricyclo[3.3.1.1(3,7)]dec-2-yl [1-[4,5-dihydro-4-(phenylmethyl)-2- thiazolyl]-2-(1H-indol-3-yl)ethyl]carbamate (5), which is selective for the CCK-A receptor (CCK-A IC50 = 125 nM, CCK-B IC50 = 2580 nM, ratio = 21). The methyleneamino and hydroxyethylene replacements, which have been used elsewhere as transition-state inhibitors of enzymes, are poor mimics of the amide in these CCK-B receptor ligands. Some of the steric, lipophilic, and hydrogen bonding properties of amide replacements incorporated into the simple amide, N-methylacetamide, have been quantified with the aid of molecular modeling. These data will contribute to the rational selection of amide bond replacements in other substrates.
本文描述了一系列化合物的化学合成及其对CCK - B和CCK - A受体的结合亲和力。在这些化合物中，CCK - B“二肽类”配体三环[3.3.1.1(3,7)]癸 - 2 - 基[R - (R*,S*)] - [2 - [[1 - (羟甲基)-2 - 苯基乙基]氨基] - 1 - (1H - 吲哚 - 3 - 基甲基)-2 - 氧代乙基]氨基甲酸酯(4)(CCK - B IC50 = 852 nM)和三环[3.3.1.1(3,7)]癸 - 2 - 基(R)-[1 - (1H - 吲哚 - 3 - 基甲基)-1 - 甲基 - 2 - 氧代 - 2 - [(2 - 苯基乙基)氨基]乙基]氨基甲酸酯(23)(CCK - B IC50 = 32 nM)的中心酰胺键被11种不同的酰胺替代物取代。这些替代物包括亚甲基氨基(CH2NH)、反向酰胺(NHCO)、酯(COO)、N - 甲基酰胺(CONMe)、硫代酰胺(CSNH)、N - 乙酰亚甲基氨基(CH2NAc)、顺式双键(CHCH)、乙烯(CH2CH2)、硫醇酯(COS)、羟乙烯(CHOHCH2)和4,5 - 二氢 - 1,3 - 噻唑。与母体酰胺相比，大多数替代物对CCK - B受体的亲和力较弱且选择性降低。然而，通过在苯乙基上连接富马酸侧链可以提高这种亲和力，例如三环[3.3.1.1(3,7)]癸 - 2 - 基 - 3 - (1H - 吲哚 - 3 - 基 - 甲基)-3 - 甲基 - 4,9 - 二氧代 - 7 - 苯基 - 5,13 - 二氧杂 - 2,8 - 二氮杂十四碳 - 10 - 烯酸酯(36)(CCK - B IC50 = 38.8 nM)。用4,5 - 二氢 - 1,3 - 噻唑替代化合物4的酰胺得到三环[3.3.1.1(3,7)]癸 - 2 - 基[1 - [4,5 - 二氢 - 4 - (苯甲基)-2 - 噻唑基]-2 - (1H - 吲哚 - 3 - 基)乙基]氨基甲酸酯(5)，其对CCK - A受体具有选择性(CCK - A IC50 = 125 nM，CCK - B IC50 = 2580 nM，比值 = 21)。亚甲基氨基和羟乙烯替代物在其他地方曾用作酶的过渡态抑制剂，在这些CCK - B受体配体中它们对酰胺的模拟效果较差。借助分子模拟对并入简单酰胺N - 甲基乙酰胺中的酰胺替代物的一些空间、亲脂性和氢键性质进行了量化。这些数据将有助于在其他底物中合理选择酰胺键替代物。
