Discovery of potent dual-tailed benzenesulfonamide inhibitors of human carbonic anhydrases im-plicated in glaucoma and in vivo profiling of their intraocular pressure lowering action.

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ID: 92785
2020
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Abstract
The design of three dual-tailed sulfonamide series 11a-g, 14a-h and 16a-e as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors are presented. All compounds were evaluated for inhibitory action against phar-macologically relevant human (h) CAs isoforms I, II, IV, and VII. Compounds 11a-g 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 moie-ties within in the ligand structure interacted directly with the hydrophobic and hydrophilic halves of the CA II active site. Compounds 11b-d and 11g were evaluated for their intraocular pressure (IOP) lower-ing effects in a rabbit model of the glaucoma. 11b and 11d showed significant efficacy when compared to the clinically used drug dorzolamide.
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Authors Fares, Mohamed;Eldehna, Wagdy M;Bua, Silvia;Lanzi, Cecilia;Lucarini, Laura;Masini, Emanuela;Peat, Thomas S;Abdel-Aziz, Hatem A;Nocentini, Alessio;Keller, Paul A;Supuran, Claudiu Trandafir;
Journal Journal of medicinal chemistry
Year 2020
DOI
10.1021/acs.jmedchem.9b02090
URL
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