Carbonic anhydrase inhibitors: synthesis of water soluble sulfonamides incorporating a 4-sulfamoylphenylmethylthiourea scaffold, with potent intraocular pressure lowering properties.
Reaction of thiophosgene with 4-aminomethyl-benzenesulfonamide afforded 4-isothiocyanatomethyl-benzenesulfonamide, which by reaction with amines, amino acids and oligopeptides, lead to a series of new sulfonamides incorporating a 4-sulfamoylphenylmethylthiourea scaffold. These new thioureas showed strong affinities towards 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, beta-phenyl-serine, alpha-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 (IOP) lowering when administered topically, as 2% solutions.
Casini
Angela
A
Università degli Studi di Firenze, Polo Scientifico, Dipartimento di Chimica, Laboratorio di Chimica Bioinorganica, Via della Lastruccia, 3, Rm. 188, 1-50019 Sesto Fiorentino (Firenze), Italy.
Scozzafava
Andrea
A
Mincione
Francesco
F
Menabuoni
Luca
L
Supuran
Claudiu T
CT
D000818:Animals; D024401:Carbonic Anhydrase I / Q000378:metabolism*; D024402:Carbonic Anhydrase II / Q000378:metabolism*; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D003315:Cornea / Q000378:metabolism; D018076:DNA, Complementary / Q000235:genetics / Q000378:metabolism; D004926:Escherichia coli / Q000201:enzymology; D005901:Glaucoma / Q000188:drug therapy; D006801:Humans; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D007429:Intraocular Pressure / Q000187:drug effects*; D008297:Male; D009883:Ophthalmic Solutions; D011487:Protein Conformation; D011817:Rabbits; D011994:Recombinant Proteins / Q000302:isolation & purification / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D013890:Thiourea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
D002257:Carbonic Anhydrase Inhibitors; D018076:DNA, Complementary; D009883:Ophthalmic Solutions; D011994:Recombinant Proteins; D013449:Sulfonamides; D024401:Carbonic Anhydrase I; D024402:Carbonic Anhydrase II; D013890:Thiourea