发现强效双头苯磺酰胺类人碳酸酐酶抑制剂可用于治疗青光眼，并对其降低眼内压作用进行体内分析。
Discovery of Potent Dual-Tailed Benzenesulfonamide Inhibitors of Human Carbonic Anhydrases Implicated in Glaucoma and in Vivo Profiling of Their Intraocular Pressure-Lowering Action.
机构信息
School of Chemistry & Molecular Bioscience, Molecular Horizons, and Illawarra Health & Medical Research Institute, University of Wollongong, Wollongong, NSW 2522, Australia.
School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia.
出版信息
J Med Chem. 2020 Mar 26;63(6):3317-3326. doi: 10.1021/acs.jmedchem.9b02090. Epub 2020 Feb 20.
The design of three dual-tailed sulfonamide series , , and as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors are presented. All compounds were evaluated for inhibitory action against pharmacologically relevant human CA isoforms I, II, IV, and VII. Compounds emerged as potent CA inhibitors against the four tested isoforms with a significant selectivity to CA II, which is implicated in glaucoma ( in the range 0.36-6.9 nM). X-ray crystallographic analysis of three compounds (, , and ) bound to CA II showed the validity of the adopted drug design strategy as specific moieties within the ligand structure interacted directly with the hydrophobic and hydrophilic halves of the CA II active site. Compounds - and were evaluated for their intraocular pressure-lowering effects in a rabbit model of glaucoma. and showed significant efficacy when compared to the clinically used drug dorzolamide.
设计了三种双尾磺酰胺系列化合物 、 和 作为碳酸酐酶（CA，EC 4.2.1.1）抑制剂。所有化合物均经过评估，以测试其对药理学上相关的人源 CA 同工酶 I、II、IV 和 VII 的抑制作用。化合物 对四种测试同工酶表现出很强的 CA 抑制作用，对 CA II 具有显著的选择性，CA II 与青光眼有关（在 0.36-6.9 nM 的范围内）。与 CA II 结合的三种化合物（ 、 和 ）的 X 射线晶体结构分析表明，所采用的药物设计策略是有效的，因为配体结构内的特定部分直接与 CA II 活性位点的疏水和亲水半部分相互作用。化合物 - 和 用于评估它们在兔青光眼模型中的降眼压效果。 和 与临床使用的药物多佐胺相比，表现出显著的疗效。
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