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Abstract #8510 Published in IGR 5-1
Carbonic anhydrase inhibitors: Synthesis of water soluble sulfonamides incorporating a 4-sulfamoylphenylmethylthiourea scaffold, with potent intraocular pressure lowering properties
Casin A; Scozzafava A; Mincione F; Menabuoni L; Supuran CTJournal of Enzyme Inhibition and Medicinal Chemistry 2002; 17: 333-343
Reaction of thiophosgene with 4-aminomethyl-benzene-sulfonamide gives 4-isothiocyanatomethyl-benzene-sulfonamide, which by reaction with amines, amino acids and oligopeptides, leads to a series of new sulfonamides incorporating a 4-sulfamoylphenyl-methylthiourea scaffold. These new thioureas showed strong affinity to isozymes I, II and IV of carbonic anhydrase (CA, EC 4.2.1.1). In vitro inhibitory potency was good (in the low nanomolar range) for the derivatives of: amino-benzoic acids, β-phenyl-serine, α-phenyl-glycine, for those incorporating hydroxy- and mercapto-amino acids (Ser, Thr, Cys and Met), hydrophobic amino acids (Val, Leu, Ile), aromatic amino acids (Phe, His, Trp, Tyr; DOPA); 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%) as sodium (carboxylate) salts, with pH values for the solutions obtained of 6.5-7.0. Furthermore, in normotensive rabbits, some of them showed an effective and prolonged intraocular pressure lowering when administered topically as 2% solutions.
Dr. C.T. Supuran, Universita degli Studi di Firenze, Dipartimento di Chimica, Laboratorio di Chimica Bioinorganica, Via della Lastruccia 3, I-50019 Sesto Fiorentino Firenze, Italy. claudiu.supuran@unifi.it
Classification:
11.5.2 Topical (Part of: 11 Medical treatment > 11.5 Carbonic anhydrase inhibitors)