Carbonic Anhydrase Inhibitors. A General Approach for the Preparation of Water-Soluble Sulfonamides Incorporating Polyamino−Polycarboxylate Tails and of Their Metal Complexes Possessing Long-Lasting, Topical Intraocular Pressure-Lowering Properties

Journal of Medicinal Chemistry
2002.0

Abstract

Reaction of polyamino-polycarboxylic acids or their dianhydrides with aromatic/heterocyclic sulfonamides possessing a free amino/imino/hydrazino/hydroxy group afforded mono- and bis-sulfonamides containing polyamino-polycarboxylic acid moieties in their molecule. The acids/anhydrides used in synthesis included IDA, NTA, EDDA, EDTA and EDTA dianhydride, DTPA and DTPA dianhydride, EGTA and EGTA dianhydride, and EDDHA, among others. All the newly prepared derivatives showed strong affinity toward isozymes I, II, and IV of carbonic anhydrase (CA). Metal complexes of the new compounds have also been prepared. Metal ions used in such preparations included di- and trivalent main-group and transition cations, such as Zn(II), Cu(II), Al(III), etc. Some of the new sulfonamides/disulfonamides obtained in this way, as well as their metal complexes, behaved as nanomolar CA inhibitors against isozymes II and IV, being slightly less effective in inhibiting isozyme I. Some of these sulfonamides as well as their metal complexes strongly lowered intraocular pressure (IOP) when applied topically, directly into the normotensive/glaucomatous rabbit eye, as 1-2% water solutions/suspensions. The good water solubility of these sulfonamide CA inhibitors, correlated with the neutral pH of their water solutions used in the ophthalmologic applications and the long duration of action of the IOP-lowering effect, makes them interesting candidates for developing novel types of antiglaucoma drugs devoid of serious topical side effects.

Knowledge Graph

Similar Paper

Carbonic Anhydrase Inhibitors. A General Approach for the Preparation of Water-Soluble Sulfonamides Incorporating Polyamino−Polycarboxylate Tails and of Their Metal Complexes Possessing Long-Lasting, Topical Intraocular Pressure-Lowering Properties
Journal of Medicinal Chemistry 2002.0
Carbonic anhydrase inhibitors: synthesis of sulfonamides incorporating dtpa tails and of their zinc complexes with powerful topical antiglaucoma properties
Bioorganic & Medicinal Chemistry Letters 2001.0
Carbonic Anhydrase Inhibitors:  Synthesis of Water-Soluble, Aminoacyl/Dipeptidyl Sulfonamides Possessing Long-Lasting Intraocular Pressure-Lowering Properties via the Topical Route
Journal of Medicinal Chemistry 1999.0
Carbonic Anhydrase Inhibitors. Synthesis of Water-Soluble, Topically Effective, Intraocular Pressure-Lowering Aromatic/Heterocyclic Sulfonamides Containing Cationic or Anionic Moieties:  Is the Tail More Important than the Ring?
Journal of Medicinal Chemistry 1999.0
Carbonic Anhydrase Inhibitors:  Water-Soluble 4-Sulfamoylphenylthioureas as Topical Intraocular Pressure-Lowering Agents with Long-Lasting Effects
Journal of Medicinal Chemistry 2000.0
Carbonic anhydrase inhibitors: N-(p-sulfamoylphenyl)-α-d-glycopyranosylamines as topically acting antiglaucoma agents in hypertensive rabbits
Bioorganic & Medicinal Chemistry Letters 2004.0
Carbonic Anhydrase Inhibitors:  Perfluoroalkyl/Aryl-Substituted Derivatives of Aromatic/Heterocyclic Sulfonamides as Topical Intraocular Pressure-Lowering Agents with Prolonged Duration of Action
Journal of Medicinal Chemistry 2000.0
Synthesis of 2-substituted-1,3,4-thiadiazole-5-sulphonamides as novel water-soluble inhibitors of carbonic anhydrase
Bioorganic & Medicinal Chemistry Letters 1991.0
Carbonic anhydrase inhibitors: Topically acting antiglaucoma sulfonamides incorporating esters and amides of 3- and 4-carboxybenzolamide
Bioorganic & Medicinal Chemistry Letters 2003.0
Carbonic anhydrase inhibitors: Design of thioureido sulfonamides with potent isozyme II and XII inhibitory properties and intraocular pressure lowering activity in a rabbit model of glaucoma
Bioorganic & Medicinal Chemistry Letters 2005.0