Highly hydrophilic 1,3-oxazol-5-yl benzenesulfonamide inhibitors of carbonic anhydrase II for reduction of glaucoma-related intraocular pressure

被引：11

作者：

Kalinin, Stanislav ^{[1
]}

Valtari, Annika ^{[2
]}

Ruponen, Marika ^{[2
]}

Toropainen, Elisa ^{[2
]}

Kovalenko, Alexander ^{[1
]}

Nocentini, Alessio ^{[3
]}

Gureev, Maxim ^{[4
]}

Dar'in, Dmitry ^{[1
]}

Urtti, Arto ^{[1
,2
,5
]}

Supuran, Claudiu T. ^{[3
]}

Krasavin, Mikhail ^{[1
]}

机构：

[1] St Petersburg State Univ, St Petersburg 199034, Russia

[2] Univ Eastern Finland, Sch Pharm, Kuopio 70211, Finland

[3] Univ Firenze, Neurofarba Dept, Florence, Italy

[4] IM Sechenov First Moscow State Med Univ, Moscow 119991, Russia

[5] Univ Helsinki, Fac Pharm, Div Pharmaceut Biosci, Drug Res Programme, Helsinki, Finland

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2019年 / 27卷 / 21期

关键词：

Glaucoma; Intraocular pressure; Hydrophilicity; Intraocular delivery; Non-corneal absorption; Carbonic anhydrase inhibitors; QUANTITATIVE-EVALUATION; PICOMOLAR INHIBITORS; SYSTEMIC ABSORPTION; PILOCARPINE; PHARMACOTHERAPY; SULFONAMIDES; CONJUNCTIVA; PROTEIN;

D O I：

10.1016/j.bmc.2019.115086

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Four inhibitors of human carbonic anhydrase II (hCA II) were designed based on the previously reported sub-nanomolar 1,3-oxazole-based sulfonamide inhibitors of the enzyme to incorporate primary and secondary amine functionality in the carboxamide side chain. The new hydrophilic compounds were found to inhibit the target isoform in sub-nanomolar to low nanomolar range with a good degree of selectivity to several other hCA isoforms. The hydrophilic character of these compounds is advantageous for intraocular residence time but not for corneal permeability which generally requires that a drug be sufficiently lipophilic. Two of the four compounds investigated, however, were found to exert comparable efficacy as 1% eye drops in PBS to that of the clinically used 2% dorzolamide (Trusopt (R)) eye drops. This indicated that the absorption of the compounds may occur via alternative route across conjunctiva and sclera.

引用

页数：8