Carbonic anhydrase inhibitors. Inhibition of mitochondrial isozyme V with aromatic and heterocyclic sulfonamides.
Carbonic anhydrase inhibitors. Inhibition of mitochondrial isozyme V with aromatic and heterocyclic sulfonamides.
复制标题
碳酸酐酶抑制剂。
DOI：
10.1021/jm031057
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发表时间：
2004
影响因子：
7.3
通讯作者：
C. Supuran
中科院分区：
文献类型：
--
作者：
D. Vullo;M. Franchi;E. Gallori;J. Antel;A. Scozzafava;C. Supuran
首次报道了一系列芳香族和杂环磺胺类药物对线粒体同工酶碳酸酐酶（CA）V（鼠源）的抑制作用。还提供了这些抑制剂的胞质同工酶CA I和CA II以及膜结合同工酶CA IV的抑制数据以供比较。检测到几种低纳摩尔CA V抑制剂（KI值在4-15 nM范围内），它们中的大多数属于酰化磺胺、脲基苯磺酰胺、1，3，4-噻二唑-2-磺酰胺和氨基苯甲酰胺类型的化合物。另一方面，临床上使用的抑制剂乙酰唑胺、醋甲唑胺、乙氧唑胺、多佐胺、布林佐胺和托吡酯是不太有效的CA V抑制剂，显示出47-63 nM范围内的抑制常数。一些研究的磺胺类药物，如脲基苯磺酰胺和酰化磺胺类药物表现出更高的亲和力CA V比其他同工酶，CA II包括，这是一个显着的结果，因为大多数化合物研究到现在为止，抑制胞质同工酶CA II更好。这些结果促使我们假设CA V的选择性抑制，或CA II和CA V的双重抑制，可能会导致开发新的药理学应用，例如在治疗或预防肥胖症，通过抑制CA介导的脂肪生成过程中的磺胺类药物。
The first inhibition study of the mitochondrial isozyme carbonic anhydrase (CA) V (of murine origin) with a series of aromatic and heterocyclic sulfonamides is reported. Inhibition data of the cytosolic isozymes CA I and CA II and the membrane-bound isozyme CA IV with these inhibitors are also provided for comparison. Several low nanomolar CA V inhibitors were detected (KI values in the range of 4-15 nM), most of them belonging to the acylated sulfanilamide, ureido-benzenesulfonamide, 1,3,4-thiadiazole-2-sulfonamide, and aminobenzolamide type of compounds. The clinically used inhibitors acetazolamide, methazolamide, ethoxzolamide, dorzolamide, brinzolamide, and topiramate on the other hand were less effective CA V inhibitors, showing inhibition constants in the range of 47-63 nM. Some of the investigated sulfonamides, such as the ureido-benzenesulfonamides and the acylated sulfanilamides showed higher affinity for CA V than for the other isozymes, CA II included, which is a remarkable result, since most compounds investigated up to now inhibited the cytosolic isozyme CA II better. These results prompt us to hypothesize that the selective inhibition of CA V, or the dual inhibition of CA II and CA V, may lead to the development of novel pharmacological applications for such sulfonamides, for example in the treatment or prevention of obesity, by inhibiting CA-mediated lipogenetic processes.