Discovery of Potent Dual-Tailed Benzenesulfonamide Inhibitors of Human Carbonic Anhydrases Implicated in Glaucoma and in Vivo Profiling of Their Intraocular Pressure-Lowering Action.,Journal of Medicinal Chemistry

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Discovery of Potent Dual-Tailed Benzenesulfonamide Inhibitors of Human Carbonic Anhydrases Implicated in Glaucoma and in Vivo Profiling of Their Intraocular Pressure-Lowering Action.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-02-07 , DOI: 10.1021/acs.jmedchem.9b02090
Mohamed Fares _{1,

2} , Wagdy M Eldehna ₃ , Silvia Bua ₄ , Cecilia Lanzi ₅ , Laura Lucarini ₅ , Emanuela Masini ₅ , Thomas S Peat ₆ , Hatem A Abdel-Aziz ₇ , Alessio Nocentini ₄ , Paul A Keller ₁ , Claudiu T Supuran ₄

Affiliation

The design of three dual-tailed sulfonamide series 11a-11g, 14a-14h, and 16a-16e 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 11a-11g emerged as potent CA inhibitors against the four tested isoforms with a significant selectivity to CA II, which is implicated in glaucoma (Ki in the range 0.36-6.9 nM). X-ray crystallographic analysis of three compounds (11a, 11d, and 11g) 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 11b-11d and 11g were evaluated for their intraocular pressure-lowering effects in a rabbit model of glaucoma. 11b and 11d showed significant efficacy when compared to the clinically used drug dorzolamide.

中文翻译：

发现青光眼中涉及的人碳酸酐酶的强效双尾苯甲磺酰胺抑制剂及其体内降眼压作用的体内分析。

介绍了三种双尾磺酰胺系列11a-11g，14a-14h和16a-16e作为碳酸酐酶（CA，EC 4.2.1.1）抑制剂的设计。评价所有化合物对药理学相关的人CA同工型I，II，IV和VII的抑制作用。化合物11a-11g作为对四种受试同工型的有效CA抑制剂出现，对CA II具有显着选择性，这与青光眼有关（Ki在0.36-6.9 nM之间）。对与CA II结合的三种化合物（11a，11d和11g）的X射线晶体学分析表明，采用的药物设计策略是有效的，因为配体结构中的特定部分与CA II活性位点的疏水和亲水部分直接相互作用。评价化合物11b-11d和11g在兔青光眼模型中的眼内降压作用。

更新日期：2020-02-20

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