在P1'位含有联苯甲基衍生物的大环异羟肟酸的发现，这是一系列具有有效细胞活性的选择性肿瘤坏死因子-α转化酶抑制剂，可抑制肿瘤坏死因子-α的释放。

Discovery of macrocyclic hydroxamic acids containing biphenylmethyl derivatives at P1', a series of selective TNF-alpha converting enzyme inhibitors with potent cellular activity in the inhibition of TNF-alpha release.

作者信息

Xue C B, He X, Corbett R L, Roderick J, Wasserman Z R, Liu R Q, Jaffee B D, Covington M B, Qian M, Trzaskos J M, Newton R C, Magolda R L, Wexler R R, Decicco C P

机构信息

DuPont Pharmaceuticals Company, Experimental Station, P.O. Box 80500, Wilmington, Delaware 19880-0500, USA.

出版信息

J Med Chem. 2001 Oct 11;44(21):3351-4. doi: 10.1021/jm0155502.

DOI:10.1021/jm0155502

PMID:11585440

Abstract

SAR exploration at P1' using an anti-succinate-based macrocyclic hydroxamic acid as a template led to the identification of several bulky biphenylmethyl P1' derivatives which confer potent porcine TACE and anti-TNF-alpha cellular activities with high selectivity versus most of the MMPs screened. Our studies demonstrate for the first time that TACE has a larger S1' pocket in comparison to MMPs and that potent and selective TACE inhibitors can be achieved by incorporation of sterically bulky P1' residues.

摘要

以基于抗琥珀酸的大环异羟肟酸为模板，在P1'处进行SAR探索，从而鉴定出几种庞大的联苯甲基P1'衍生物，这些衍生物对猪TACE具有强效活性，对肿瘤坏死因子-α具有细胞活性，相对于大多数筛选的基质金属蛋白酶具有高选择性。我们的研究首次证明，与基质金属蛋白酶相比，TACE具有更大的S1'口袋，并且通过引入空间庞大的P1'残基可以实现强效且选择性的TACE抑制剂。