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Bioorg Med Chem Lett. 2013 Apr 1;23(7):2027-30. doi: 10.1016/j.bmcl.2013.02.024. Epub 2013 Feb 13.
Substitution at the alpha center of the known human arginase inhibitor 2-amino-6-boronohexanoic acid (ABH) is acceptable in the active site pockets of both human arginase I and arginase II. In particular, substituents with a tertiary amine linked via a two carbon chain show improved inhibitory potency for both enzyme isoforms. This potency improvement can be rationalized by X-ray crystallography, which shows a water-mediated contact between the basic nitrogen and the carboxylic acid side chain of Asp200, which is situated at the mouth of the active site pocket of arginase II (Asp181 in arginase I). We believe that this is the first literature report of compounds with improved arginase inhibitory activity, relative to ABH, and represents a promising starting point for further optimization of in vitro potency and the identification of better tool molecules for in vivo investigations of the potential pathophysiological roles of arginases.
在已知的人类精氨酸酶抑制剂 2-氨基-6-硼代己酸（ABH）的α 中心进行取代，在人类精氨酸酶 I 和精氨酸酶 II 的活性口袋中都是可以接受的。特别是，通过两个碳链连接的带有叔胺的取代基对两种酶同工酶的抑制活性都有提高。这种活性提高可以通过 X 射线晶体学来合理化，其显示了基本氮和位于精氨酸酶 II 活性口袋入口处的天冬氨酸 200（精氨酸酶 I 中的天冬氨酸 181）的羧酸侧链之间的水介导的接触。我们相信，这是文献中首次报道与 ABH 相比具有提高的精氨酸酶抑制活性的化合物，为进一步优化体外活性以及鉴定更好的工具分子以研究精氨酸酶的潜在病理生理作用提供了有希望的起点。
