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Abstract #15759 Published in IGR 2-3
Carbonic anhydrase inhibitors: perfluoroalkyl/aryl-substituted derivatives of aromatic/heterocyclic sulfonamides as topical intraocular pressure-lowering agents with prolonged duration of action
Scozzafava A; Menabuoni L; Mincione F; Briganti F; Mincione G; Supuran CTJournal of Medicinal Chemistry 2000; 43: 4542-4551
The reaction of perfluoroalkyl/arylsulfonyl chlorides or perfluoroalkyl/arylcarbonyl chlorides with aromatic/heterocyclic sulfonamides possessing a free amino/imino/hydrazino/hydroxy group afforded compounds with the general formula C(x)()F(y)()Z-A-SO(2)NH(2), where Z = SO(2)NH, SO(3), CONH, or CO(2) and A = aromatic/heterocyclic moiety. The sulfonyl chlorides used in synthesis included: CF(3)SO(2)Cl, n-C(4)F(9)SO(2)Cl, n-C(8)F(17)SO(2)Cl, and C(6)F(5)SO(2)Cl, whereas the acyl chlorides were C(8)F(17)COCl and C(6)F(5)COCl. A total of 25 different sulfonamides have been derived by means of the above-mentioned perfluorosulfonyl/acyl halides. This new series of sulfonamides showed strong affinity with isozymes I, II, and IV of carbonic anhydrase (CA). For a given sulfonamide derived by the above procedures, inhibitory power was greater for the alkyl/arylsulfonylated compounds, compared to the corresponding perfluoroalkyl/arylcarbonylated ones. In vitro inhibitory activity generally increased with the number of carbon atoms in the molecule of the acylating/sulfonylating agent, with a maximum for the perfluorophenylsulfonylated and perfluorobenzoylated derivatives. Some of the prepared CA inhibitors displayed very good water solubility (in the range of 2%) and strongly lowered intraocular pressure (IOP) when applied topically, directly into normotensive/glaucomatous rabbit eyes, as 2% water solutions. The good water solubility of these new classes of CA inhibitors correlated with the neutral pH of their solutions used in ophthalmological applications, makes them attractive candidates for developing novel types of antiglaucoma drugs devoid of unpleasant ocular side-effects.
Dr. A. Scozzafava, Laboratorio di Chimica Inorganica e Bioinorganica, Universita degli Studi di Firenze, Via Gino Capponi 7, I-50121 Florence, Italy
Classification:
11.5.2 Topical (Part of: 11 Medical treatment > 11.5 Carbonic anhydrase inhibitors)
