Scozzafava A, Menabuoni L, Mincione F, Briganti F, Mincione G, Supuran C T
Laboratorio di Chimica Inorganica e Bioinorganica, Università degli Studi, Via Gino Capponi 7, I-50121 Florence, Italy.
J Med Chem. 1999 Jul 15;42(14):2641-50. doi: 10.1021/jm9900523.
Reaction of several aromatic/heterocyclic sulfonamides containing a free amino, imino, hydrazino, or hydroxyl group, with 2, 3-pyridinedicarboxylic anhydride or 2,6-pyridinedicarboxylic acid in the presence of carbodiimide derivatives, afforded two series of water-soluble (as hydrochloride, triflate, or carboxylate salts) compounds. The new derivatives were assayed as inhibitors of the zinc enzyme carbonic anhydrase (CA) and more precisely of three of its isozymes, CA I, II (cytosolic forms), and IV (membrane-bound form), involved in important physiological processes. Efficient inhibition was observed against all three isozymes, but especially against CA II and IV (in nanomolar range), the two isozymes known to play a critical role in aqueous humor secretion within the ciliary processes of the eye. Some of the best inhibitors synthesized were applied as 2% water solutions directly into the eye of normotensive and glaucomatous albino rabbits. Very strong and long-lasting intraocular pressure (IOP) lowering was observed with many of them. This result prompted us to reanalyze the synthetic work done by other groups for the design of water-soluble, topically effective antiglaucoma sulfonamides. According to these researchers, the IOP-lowering effect is due to the intrinsic nature of the specific heterocyclic sulfonamide considered, among which the thienothiopyran-2-sulfonamide derivatives represent the best-studied case. Indeed, the first agents developed for topical application, such as dorzolamide, are derivatives of this ring system. To prove that the tail (in this case the pyridinecarboxylic moieties) conferring water solubility to a sulfonamide CA inhibitor is more important than the ring to which the sulfonamido group is grafted, we also prepared dorzolamide derivatives incorporating such moieties. These new compounds possess good water solubility as hydrochloride or carboxylate salts, balanced by a relatively modest lipid solubility. They are strong CA II inhibitors and are able to lower IOP in experimental animals more than the parent derivatives. Our conclusion is that the tail conferring water solubility to such an enzyme inhibitor is more important for topical activity as an antiglaucoma drug, than the heterocyclic/aromatic ring to which the sulfonamido moiety is grafted.
几种含有游离氨基、亚氨基、肼基或羟基的芳香族/杂环磺酰胺，在碳二亚胺衍生物存在下，与2,3-吡啶二甲酸酐或2,6-吡啶二甲酸反应，得到了两个系列的水溶性（盐酸盐、三氟甲磺酸盐或羧酸盐形式）化合物。这些新衍生物被作为锌酶碳酸酐酶（CA）的抑制剂进行了测定，更确切地说是对其三种同工酶CA I、II（胞质形式）和IV（膜结合形式）进行了测定，这些同工酶参与重要的生理过程。观察到对所有三种同工酶都有高效抑制作用，但对CA II和IV（在纳摩尔范围内）的抑制作用尤为明显，这两种同工酶在眼睫状体房水分泌中起关键作用。合成的一些最佳抑制剂以2%的水溶液直接应用于正常血压和青光眼白化兔的眼中。其中许多抑制剂都观察到了非常强烈且持久的眼压降低效果。这一结果促使我们重新分析其他研究小组为设计水溶性、局部有效的抗青光眼磺酰胺所做的合成工作。根据这些研究人员的说法，眼压降低效果归因于所考虑的特定杂环磺酰胺的内在性质，其中噻吩并噻喃-2-磺酰胺衍生物是研究得最为充分的例子。事实上，最早开发用于局部应用的药物，如多佐胺，就是这个环系的衍生物。为了证明赋予磺酰胺类CA抑制剂水溶性的尾部（在这种情况下是吡啶羧酸部分）比连接磺酰胺基的环更重要，我们还制备了含有此类部分的多佐胺衍生物。这些新化合物作为盐酸盐或羧酸盐具有良好的水溶性，同时脂溶性相对适中。它们是强效的CA II抑制剂，并且在实验动物中比母体衍生物更能降低眼压。我们的结论是，赋予这种酶抑制剂水溶性的尾部对于作为抗青光眼药物的局部活性而言，比连接磺酰胺部分的杂环/芳香环更为重要。
