Carbonic Anhydrase Inhibitors:  Water-Soluble 4-Sulfamoylphenylthioureas as Topical Intraocular Pressure-Lowering Agents with Long-Lasting Effects

Abstract

A series of sulfonamides has been obtained by reaction of 4-isothiocyanatobenzenesulfonamide with amines, amino acids, and oligopeptides. The new thiourea 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 (in the low-nanomolar range) for the derivatives of beta-phenylserine and alpha-phenylglycine, for those incorporating hydroxy and mercapto amino acids (Ser, Thr, Cys, Met), hydrophobic amino acids (Val, Leu, Ile), aromatic amino acids (Phe, His, Trp, Tyr, DOPA), and dicarboxylic amino acids as well as di/tri/tetrapeptides among others. Such CA inhibitors displayed very good water solubility (in the range of 2-3%) mainly as sodium (carboxylate) salts, with pH values of the obtained solutions being 6.5-7.0. Some of these preparations (such as the derivatives of Ser, beta-Ph-Ser, Leu, Asn, etc.) strongly lowered intraocular pressure (IOP) when applied topically, directly into 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, Arg, and oligopeptidyl thiourea derivatives showed reduced efficacy when administered topically. This may be due to the very hydrophilic nature of some of these compounds, whereas inhibitors with balanced hydro- and liposolubility also showed optimal in vivo effects. The interesting pharmacological properties of this new type of CA inhibitors, correlated with the neutral pH of their solutions used in ophthalmologic applications, make them attractive candidates for developing novel antiglaucoma drugs devoid of major ocular side effects.

Carbonic anhydrase inhibitors

“…This approach has been developed in our laboratory [46][47][48][49][50][51][52][53][54][55][56][57][58][59][60] and consists in using well-known aromatic/ heterocyclic sulfonamide scaffolds (of type A-Y) to which tails that will induce water solubility are attached at the amino, hydroxy, imino, or hydrazino moieties contained in the precursor sulfonamides A-Y.…”

“…[46][47][48][49][50][51][52][53][54][55][56][57][58][59][60] Tails that were introduced in the molecules of such new CAIs contained either moieties protonable at endocyclic nitrogen atoms (such as pyridine-or quinoline rings 30-35), or at amino groups belonging to amino acids and some of their derivatives (such as glycine, b-alanine, GABA, sarcosine, creatine, diethylenetriaminopentaacetic acid (dtpa), or glycyl-glycine moieties of types 36-42), as well as perfluoroalkyl/aryl moieties (which are not protonable at pH values in the neutral range, of types [43][44][45][46][47][48]. The water solubility of the first type of such derivatives is assured by formation of salts with hydrochloric, trifluoroacetic or triflic acid, or by formation of sodium salts, for the derivatives possessing carboxylic acid moieties (tails of types 34 or 41).…”

“…For instance, 30C should be the isonicotinoylamido derivative of sulfanilamide, 36M the glycinamido derivative of 5-amino-1,3,4-thiadiazole-2-sulfonamide, etc. [46][47][48][49][50][51][52][53][54][55][56][57][58][59][60] The main advantages of this over the ring approach are that the first is much more simple than the second, and it allows a parallel type synthesis easily, so that a large number of different derivatives may be prepared, and their physico-chemical properties modulated in such a way as to assure the desired pharmacological properties. By choosing different tails, it is possible to attain the much desired water solubility of these CAIs (as salts of acids or bases) at pH values in the neighborhood of neutrality, avoiding thus the irritation problems observed with the strongly acidic dorzolamide solutions.…”

Design, synthesis and biological evaluation ofN-(5-methyl-isoxazol-3-yl/1,3,4-thiadiazol-2-yl)-4-(3-substitutedphenylureido) benzenesulfonamides as human carbonic anhydrase isoenzymes I, II, VII and XII inhibitors

“…The inhibition constants were obtained by non-linear least-squares methods using the ChengPrusoff equation, and represent the mean from at least three different determinations. The human isoforms hCA I, II, VII and XII were recombinant enzymes produced as described earlier in our laboratory [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] .…”

“…All the synthesized compounds (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26) were studied for the inhibition of four CA isozymes of human origin, i.e. hCA I, hCA II, hCA VII and hCA XII ( Table 1).…”