Benzoylalanine-derived ketoamides carrying vinylbenzyl amino residues:: Discovery of potent water-soluble calpain inhibitors with oral bioavailability
Benzoylalanine-derived ketoamides carrying vinylbenzyl amino residues:: Discovery of potent water-soluble calpain inhibitors with oral bioavailability
复制标题
DOI：
10.1021/jm0210717
复制
发表时间：
2003-06-05
影响因子：
7.3
通讯作者：
Möller, A
中科院分区：
文献类型：
--
作者：
Lubisch, W;Beckenbach, E;Möller, A
制备新型苯甲酰丙氨酸衍生的酮酰胺并评价其对钙蛋白酶I的抑制作用。在P-2-P-3区域携带乙烯基苄基氨基残基的衍生物在纳摩尔浓度下抑制钙蛋白酶，因此代表了一类新的非肽钙蛋白酶抑制剂。所选择的实施例表现出改善的药代动力学特征，包括改善的水溶性和代谢稳定性。特别地，这些钙蛋白酶抑制剂在大鼠中显示口服生物利用度，如N-（1-苄基-2-氨基甲酰基-2-氧代乙基）-2-[E-2-（4-二乙基氨基甲基苯基）乙烯-1-基]苯甲酰胺（5d）所证明的。在大鼠的液压冲击模型中，评价密切相关的衍生物N-（1-氨基甲酰基-1-氧代己-1-基）-2-[E-2-（4-二甲基氨基甲基苯基）-乙烯-1-基]苯甲酰胺（5 b）在实验性创伤性脑损伤后的神经保护功效。当在损伤后给药时，5 b使受损神经元的数量减少了41%，这一结果与钙蛋白酶抑制剂的神经保护功效一致。
Novel benzoylalanine-derived ketoamides were prepared and evaluated for calpain I inhibition. Derivatives carrying vinylbenzyl amino residues in the P-2-P-3 region inhibited calpain in nanomolar concentrations and thus represent a novel class of nonpeptidic calpain inhibitors. Selected examples exhibited an improved pharmacokinetic profile including improved water-solubility and metabolic stability. In particular, these calpain inhibitors showed oral bioavailability in rats as demonstrated by N-(1-benzyl-2-carbamoyl-2-oxoethyl)-2-[E-2-(4-diethylaminomethylphenyl)ethen-1-yl]benzamide (5d). The closely related derivative N-(1-carbamoyl-1-oxohex-1-yl)-2-[E-2-(4-dimethylaminomethylphenyl)-ethen-1-yl]benzamide (5b) was evaluated for neuroprotective efficacy after experimental traumatic brain injury in a fluid percussion model in rats. When administered after injury, 5b reduced the number of damaged neurons by 41%, and this result would be in line with the suggested neuroprotective efficacy of calpain inhibition.