泊司他汀，一种脯氨酰内肽酶的新型抑制剂。VIII. 非肽类泊司他汀类似物的内肽酶抑制活性。

Poststatin, a new inhibitor of prolyl endopeptidase. VIII. Endopeptidase inhibitory activity of non-peptidyl poststatin analogues.

作者信息

Tsuda M, Muraoka Y, Nagai M, Aoyagi T, Takeuchi T

机构信息

Institute of Microbial Chemistry, Tokyo, Japan.

出版信息

J Antibiot (Tokyo). 1996 Oct;49(10):1022-30. doi: 10.7164/antibiotics.49.1022.

DOI:10.7164/antibiotics.49.1022

PMID:8968396

Abstract

Non-peptidyl postatin analogues, (S)-N-substituted-2-[2-(1-acylpyrrolidinyl)]-2-oxoacetamides were synthesized and examined for their inhibitory activity against prolyl endopeptidase and cathepsin B in vitro. Many compounds showed stronger activity than natural poststatin, a pentapeptide. Among them, (S)-N-cyclohexyl-2-oxo-2-[2-(1-(3-phenoxybenzoyl)pyrrolidinyl)]ace tamide (22) and (S)-N-cyclohexyl-2-[2-(1-(2-naphthoyl)pyrrolidinyl)]-2-oxoacetamide++ + (19) indicated IC50 value of 5.8 and 8.2 ng/ml for prolyl endopeptidase inhibition respectively. None of these compounds possess significant inhibitory activities against cathepsin B, a cysteine protease. These results indicate that these compounds are more selective inhibitors against prolyl endopeptidase than is natural poststatin.

摘要

合成了非肽基波他汀类似物，即(S)-N-取代-2-[2-(1-酰基吡咯烷基)]-2-氧代乙酰胺，并在体外检测了它们对脯氨酰内肽酶和组织蛋白酶B的抑制活性。许多化合物表现出比天然五肽波他汀更强的活性。其中，(S)-N-环己基-2-氧代-2-[2-(1-(3-苯氧基苯甲酰基)吡咯烷基)]乙酰胺(22)和(S)-N-环己基-2-[2-(1-(2-萘甲酰基)吡咯烷基)]-2-氧代乙酰胺(19)对脯氨酰内肽酶抑制的IC50值分别为5.8和8.2 ng/ml。这些化合物对组织蛋白酶B（一种半胱氨酸蛋白酶）均无显著抑制活性。这些结果表明，与天然波他汀相比，这些化合物是对脯氨酰内肽酶更具选择性的抑制剂。