ESTER AND AMIDE DERIVATIVES OF E64C AS INHIBITORS OF PLATELET CALPAINS
ESTER AND AMIDE DERIVATIVES OF E64C AS INHIBITORS OF PLATELET CALPAINS
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DOI：
10.1021/jm00089a015
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发表时间：
1992-05-29
影响因子：
7.3
通讯作者：
DETWILER, TC
中科院分区：
文献类型：
--
作者：
HUANG, ZY;MCGOWAN, EB;DETWILER, TC
合成了E64c的酯和酰胺衍生物，(+)-(2S，3S)-3-[[(S)-3-methyl-1-[(3-methylbutyl)carbamoyl]butyl]carbamoyl]-2-oxiranecarboxylic酸，一种钙蛋白酶的抑制剂，并测试了其对裂解细胞中的钙蛋白酶的抑制能力、进入完整细胞的能力以及对完整细胞中的钙蛋白酶的抑制能力。酯类化合物主要来自卤代醇和体积增大的醇类化合物。从乙基到三氟乙基的卤素取代酯的抑制效力没有明显的差异，这表明这类酯的易水解性对活性并不重要。唯一活性减弱的酯是最大的Z-亮氨酰-去亮氨酸乙酯，其活性约为乙酯E64d的5%。氨基酸酯的酰胺类化合物的活性也有所减弱。为了探索将E64c衍生物靶向于特定细胞的可能性，对E64c与5-羟色胺的酯类和酰胺类化合物进行了测试，这一原理是基于血小板主动摄取5-羟色胺的机制可能选择性地将药物浓缩在血小板中。酯和酰胺都抑制裂解细胞中的钙蛋白酶，但只有酯在完整细胞中被抑制。与乙酯相比，5-羟色胺酯在进入血小板方面没有优势。
Ester and amide derivatives of E64c, (+)-(2S,3S)-3-[[(S)-3-methyl-1-[(3-methylbutyl)carbamoyl]butyl]carbamoyl]-2-oxiranecarboxylic acid, an inhibitor of calpains, were synthesized and tested for ability to inhibit calpain in lysed cells, ability to enter intact cells, and ability to inhibit calpain in intact cells. The esters were from halogen-substituted alcohols and alcohols with increasing size. There were no appreciable differences in the inhibitory potency of any of the halogen-substituted esters from ethyl to trifluoroethyl, indicating that ease of hydrolysis of this class of ester is not important for activity. The only ester with impaired activity was the largest, Z-leucyl-norleucyl, which was about 5% as effective as the ethyl ester, E64d. Amides of amino acid esters also had impaired activity. To explore the possibility of targeting E64c derivatives to specific cells, esters and amides of E64c with 5-hydroxytryptamine were tested on the rationale that the active 5-hydroxytryptamine uptake mechanism of platelets might selectively concentrate the drug in platelets. Both the ester and amide inhibited calpain in lysed cells, but only the ester inhibited in intact cells. The 5-hydroxytryptamine ester showed no advantage over the ethyl ester in entering platelets.