Abstract

The synthesis and carbonic anhydrase (CA; EC 4.2.1.1) activating effects of a series of oxime ether-based amino alcohols towards four human (h) CA isoforms expressed in human brain, hCA I, II, IV and VII, are described. Most investigated amino alcohol derivatives induced a consistent activation of the tested CAs, with K_As spanning from a low micromolar to a medium nanomolar range. Specifically, hCA II and VII, putative main CA targets when central nervous system (CNS) diseases are concerned, were most efficiently activated by these oxime ether derivatives. Furthermore, a multitude of selective hCA VII activators were identified. As hCA VII is one of the key isoforms involved in brain metabolism and other brain functions, the identified potent and selective hCA VII activators may be considered of interest for investigations of various therapeutic applications or as lead compounds in search of even more potent and selective CA activators.

摘要

描述了一系列基于肟醚的氨基醇对人脑中表达的四种人（h）CA异构体hCA I，II，IV和VII的合成和碳酸酐酶（CA; EC 4.2.1.1）的激活作用。大多数研究的氨基醇衍生物均以K _A诱导了被测CA的一致活化。范围从低微摩尔到中等纳摩尔。具体而言，当涉及中枢神经系统（CNS）疾病时，hCA II和VII是假定的主要CA靶标，这些肟醚衍生物可最有效地激活它们。此外，鉴定了多种选择性hCA VII活化剂。由于hCA VII是参与大脑代谢和其他脑功能的关键同工型之一，因此，已鉴定出的有效和选择性hCA VII激活剂可能被认为是研究各种治疗应用或作为寻找更有效和选择性CA的先导化合物感兴趣激活剂。