Carbonic anhydrase inhibitors with strong topical antiglaucoma properties incorporating a 4-(2-aminopyrimidin-4-yl-amino)-benzenesulfonamide scaffold.
Reaction of 4-(2-amino-pyrimidin-4-yl-amino)-benzenesulfonamide with alkyl/aryl-sulfonyl halides, acyl halides or arysulfonyl isocyanates afforded a series of derivatives which were tested for inhibition of three carbonic anhydrase (CA) isozymes. These compounds were designed in such a way as to (i) strongly inhibit several CA isozymes involved in aqueous humor secretion within the eye (such as CA II and CA IV), and (ii) to possess a pharmacological profile that allows easy penetration through the cornea, when administered as eye drops in solution or suspension, constituting thus a valuable therapeutic approach for glaucoma. Several of the obtained inhibitors showed low nanomolar affinities for the two isozymes involved in aqueous humor secretion, CA II and CA IV. Furthermore, in normotensive and hypertensive rabbits, some of them showed an effective and prolonged intraocular pressure (IOP) lowering when administered topically, as 2% suspensions/solutions.
D000287:Administration, Topical; D000818:Animals; D024402:Carbonic Anhydrase II / Q000037:antagonists & inhibitors; D030741:Carbonic Anhydrase IV / Q000037:antagonists & inhibitors; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D005123:Eye / Q000166:cytology / Q000378:metabolism; D005901:Glaucoma / Q000188:drug therapy*; D006973:Hypertension; D007429:Intraocular Pressure / Q000187:drug effects; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000737:chemistry; D011817:Rabbits; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry; D014018:Tissue Distribution; D000096926:Benzenesulfonamides
D024402:Carbonic Anhydrase II; D030741:Carbonic Anhydrase IV; D002257:Carbonic Anhydrase Inhibitors; D007527:Isoenzymes; D011743:Pyrimidines; D013449:Sulfonamides; C475817:4-(2-aminopyrimidin-4-yl-amino)-benzenesulfonamide; D000096926:Benzenesulfonamides