Carbonic anhydrase inhibitors: Perfluoroalkyl/aryl-substituted derivativesof aromatic/heterocyclic sulfonamides as topical intraocular pressure-lowering agents with prolonged duration of action

Reaction of perfluoroalky/arylsulfonyl chlorides or perfluoroalkyl/arylcarb onyl chlorides with aromatic/heterocyclic sulfonamides possessing a free am ino/imino/hydrazino/hydroxy group afforded compounds with the general formu la C(x)F(y)Z-A-SO2NH2, where Z = SO2NH, SO3, CONH, or CO2 and A = aromatic/ heterocyclic moiety. The sulfonyl chlorides used in synthesis included: CF3 SO2Cl, n-C4F9SO2Cl, n-C8F17SO2Cl, and C6F5SO2Cl, whereas the acyl chlorides were C8F17COCl and C6F5COCl. A total of 25 different sulfonamides have bee n derivatized by means of the above-mentioned perfluorosulfonyl/acyl halide s. These new series of sulfonamides showed strong affinities toward isozyme s I, II, and TV of carbonic anhydrase (CA). For a given sulfonamide derivat ized by the above procedures, inhibitory power was greater for the alkyl/ar ylsulfonylated compounds, as compared to the corresponding perfluoroalky/ar ylcarbonylated ones. In vitro inhibitory activity generally increased with the number of carbon atoms in the molecule of the acylating/sulfonylating a gent, with a maximum for the perfluorophenylsulfonylated and perfluorobenzo ylated derivatives. Some of the prepared CA inhibitors displayed very good water solubility (in the range of 2%) and strongly lowered intraocular pres sure (IOP) when applied topically, directly into the normotensive/glaucomat ous rabbit eye, as 2% water solutions. The good water solubility of these n ew classes of CA inhibitors, correlated with the neutral pH of their soluti ons used in the ophthalmologic applications, makes them attractive candidat es for developing novel types of antiglaucoma drugs devoid of unpleasant oc ular side effects.