Carbonic anhydrase inhibitors: Water-soluble 4-sulfamoylphenylthioureas astopical intraocular pressure-lowering agents with long-lasting effects

A series of sulfonamides has been obtained by reaction of 4-isothiocyanatob enzenesulfonamide with amines, amino acids, and oligopeptides. The new thio urea derivatives showed strong affinities toward isozymes I, II, and IV of carbonic anhydrase (CA, EC 4.2.1.1), In vitro inhibitory power was good tin the low-nanomolar range) for the derivatives of beta -phenylserine and alp ha -phenylglycine, for those incorporating hydroxy and mercapto amino acids (Ser, Thr, Cys, Met), hydrophobic amino acids (Val, Leu, Ile), aromatic am ino acids (Phe, His, Trp, Tyr, DOPA), and dicarboxylic amino acids as well as di/tri/tetrapeptides among others. Such CA inhibitors displayed very goo d water solubility tin the range of 2-3%) mainly as sodium (carboxylate) sa lts, with pH values of the obtained solutions being 6.5-7.0. Some of these preparations (such as the derivatives of Ser, B-Ph-Ser, Leu, Asn, etc.) str ongly lowered intraocular pressure (IOP) when applied topically, directly i nto the normotensive/glaucomatous rabbit eye, as 2% water solutions. It is interesting to note that not all the powerful CA inhibitors designed in the present study showed topical IOP-lowering effects (such as, for instance, the Cys and Lys derivatives, devoid of such properties) whereas the Pro, Ar g, and oligopeptidyl thiourea derivatives showed reduced efficacy when admi nistered topically. This may be due to the very hydrophilic nature of some of these compounds, whereas inhibitors with balanced hydro- and liposolubil ity also showed optimal in vivo effects. The interesting pharmacological pr operties of this new type of CA inhibitors, correlated with the neutral pH of their solutions used in ophthalmologic applications, make them attractiv e candidates for developing novel antiglaucoma drugs devoid of major ocular side effects.