基于糖基结构的新型碳酸酐酶II抑制剂设计、合成及抗青光眼活性评价

Although the treatment of glaucoma with inhibitors of the metallo-enzyme carbonic anhydrase is very effective in reducing elevated intraocular pressure(IOP), the systemic administration of drugs such as acetazolamide AZA, methazolamide MZA leads to unpleasant side effects due to inhibition of the enzyme present in other tissues (kidneys, red cells, stomach, etc.) than the eye. In most cases, oral CA inhibitors are used only as a last resort. For more than 40 years, it was considered that CA inhibitors could only be given sistemically. Important advances in this field have been then achieved by discovering the clinically used, topically effective antiglaucoma sulfonamide, dorzolamide and brinzolamide..However, dorzolamide and brinzolamide are not soluble enough at neutral pH and must be used as a suspension (brinzolamide) or must be solubilized as hydrochloride salt (dorzolamide) and as a consequence, the pH of the solution is rather acidic (around 5.5). Both these properties lead to undesired side effects of these two antiglaucoma drugs such as blurred vision, eye redening and irritation, and so on.. We have explored on the other hand an alternative approach for the design of topically acting antiglaucoma sulfonamides, which consists in attaching tails that will induce the desired physico-chemical properties (such as for example water solubility, good penetrability through the cornea, etc.) to scaffolds of aromatic/heterocyclic sulfonamides also incorporating derivatizable moieties of the amino type.. Many tails have been used for the design of topically acting sulfonamide CA inhibitor antiglaucoma agents, but no sugar moieties have been incorporated up to now in such compounds. Due to the highly hydrophilic character of such sugar moieties, one may expect a good water solubility for sulfonamides incorporating them, a feature desirable for topically acting drugs to be administered directly into the eye..Thus, it was easy to formulate them as eye-drops at neutral pH values, which constitutes a very desirable pharmacological feature for topically acting antiglaucoma drugs. Thus, we will explore the possibility of synthesizing sugar-containing sulfonamides, prepare a series of such derivatives possessing glucuronic acid tails, and study their in vitro CA inhibitory properties against isozymes hCA I and hCA II. Some of the most effective CA inhibitors obtained will be investigated in vivo, in rabbits with high intraocular pressure (IOP), in order to detect compounds useful as topically acting antiglaucoma drugs.

本项目针对CAII抑制剂需同时具备高水溶性和高角膜透过率这一难点问题，从CAII的结构特征出发，结合计算机辅助技术预测结果，设计由多种糖基结构修饰的新型CAII抑制剂，使目标化合物具有好的亲水性，可配置成能局部用药的水溶液形式，以避免口服用药造成的全身副作用，同时可使目标化合物在睫状体处达到治疗浓度。因糖基结构引入使目标化合物避免使用盐酸盐的形式，消除了对眼睛的刺激，因此含糖片段的磺胺类化合物克服了已上市的抗青光眼药物的缺点。项目通过扎实的糖化学合成技术，构建新颖的结构多样性化合物库，经酶水平的活性测试，评价选择性抑制CAII的作用能力，总结较为系统的构效关系。进一步开展水溶性试验、角膜渗透性试验和家兔体内降眼压实验，深入讨论糖基结构的生物学功能。本项目为建立与睫状体CAII产生特异结合和有效作用的抑制剂的发现策略提供一条科学有效的新思路。

本项目针对CAII抑制剂需同时具备高水溶性和高角膜透过率这一难点问题，从CAII的结构特征出发，结合计算机辅助技术预测结果，设计由多种糖基结构修饰的新型CAII抑制剂，使目标化合物具有好的亲水性，可配置成能局部用药的水溶液形式（大于1%），避免了口服用药造成的全身副作用。因糖基结构引入使目标化合物避免使用盐酸盐的形式，糖类目标化合物在水溶液中的pH接近中性，消除了对眼睛的刺激，因此含糖片段的磺胺类化合物克服了已上市的抗青光眼药物的缺点。项目通过新型的糖化学合成技术，制备了多个系列的目标化合物，后经酶水平的活性测试，评价选择性抑制CAII的作用能力。进一步开展水溶性试验、pH测试和家兔体内降眼压实验，发现了一类具有进一步研究价值的抗青光眼先导分子。