First insight into structure-activity relationships of selective meprin β inhibitors
First insight into structure-activity relationships of selective meprin β inhibitors
复制标题
DOI：
10.1016/j.bmcl.2017.04.012
复制
发表时间：
2017-06-01
影响因子：
2.7
通讯作者：
Buchholz, Mirko
中科院分区：
文献类型：
--
作者：
Ramsbeck, Daniel;Hamann, Antje;Buchholz, Mirko
虾红素蛋白酶 meprin a 和 beta 是治疗肾衰竭、纤维化或炎症性肠病等疾病的新兴药物靶点。然而，迄今为止报道的这两种蛋白酶的抑制剂很少。从 NNGH 作为先导结构开始，对 meprin β 抑制剂的结构-活性关系进行了详细阐述，得到了具有较低纳摩尔范围活性的化合物。考虑到 meprin 0 对 P1' 位酸性残基的偏好，对化合物进行了优化。与其他结构相关的金属蛋白酶（例如 MMP-2 或 ADAM10）相比，酸性修饰可诱导有效的抑制和超过 100 倍的选择性。 (C) 2017 Elsevier Ltd. 保留所有权利。
The astacin proteases meprin a and beta are emerging drug targets for treatment of disorders such as kidney failure, fibrosis or inflammatory bowel disease. However, there are only few inhibitors of both proteases reported to date. Starting from NNGH as lead structure, a detailed elaboration of the structure-activity relationship of meprin beta inhibitors was performed, leading to compounds with activities in the lower nanomolar range. Considering the preference of meprin 0 for acidic residues in the P1' position, the compounds were optimized. Acidic modifications induced potent inhibition and >100-fold selectivity over other structurally related metalloproteases such as MMP-2 or ADAM10. (C) 2017 Elsevier Ltd. All rights reserved.