Carbonic anhydrase inhibitors: synthesis of water-soluble, topically effective intraocular pressure lowering aromatic/heterocyclic sulfonamides containing 8-quinoline-sulfonyl moieties: is the tail more important than the ring?
Reaction of 20 aromatic/heterocyclic sulfonamides containing a free amino, imino, hydrazino or hydroxyl group, with 8-quinoline-sulfonyl chloride afforded a series of water-soluble (as hydrochloride or triflate salts) compounds. The new derivatives were assayed as inhibitors of the zinc enzyme carbonic anhydrase (CA), and more precisely of three of its isozymes, CA I, II (cytosolic forms) and IV (membrane-bound form), involved in important physiological processes. Efficient inhibition was observed against all three isozymes, but especially against CA II (in nanomolar range), which is the isozyme known to play a critical role in aqueous humor secretion within the ciliary processes of the eye. Some of the best inhibitors synthesized were topically applied as 2% water solutions onto the eye of normotensive and glaucomatous albino rabbits, when strong and long-lasting intraocular pressure (IOP) lowering was observed with many of them. This result prompted us to reanalyze the synthetic work done by other groups for the design of water soluble, topically effective antiglaucoma sulfonamides. According to these researchers, the IOP lowering effect is due to the intrinsic nature of the specific heterocyclic sulfonamide considered, among which the thienothiopyran-2-sulfonamide derivatives represent the best studied case. Indeed, the first agents developed for such applications, such as dorzolamide, are derivatives of this ring system. In order to prove that the tail (in this case the 8-quinoline-sulfonyl moiety) conferring water solubility to a sulfonamide CA inhibitor is more important than the ring to which the sulfonamido group is grafted, we also prepared a dorzolamide derivative to which the 8-quinoline-sulfonyl moiety was attached. This new compound is quite water soluble as hydrochloride salt, behaves as a strong CA II inhibitor, and fared better than the parent molecule in lowering IOP in experimental animals. Thus, the tail conferring water solubility to such an enzyme inhibitor is more important for its topical activity as antiglaucoma drug than the heterocyclic/aromatic ring to which the sulfonamido moiety is grafted.
Borras
J
J
Universidad de Valencia, Facultad de Farmacia, Departamento de Quimica Inorganica, Spain.
Scozzafava
A
A
Menabuoni
L
L
Mincione
F
F
Briganti
F
F
Mincione
G
G
Supuran
C T
CT
D000287:Administration, Topical; D000818:Animals; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002256:Carbonic Anhydrases / Q000378:metabolism*; D003315:Cornea / Q000201:enzymology / Q000378:metabolism; D005901:Glaucoma / Q000188:drug therapy; D006801:Humans; D066298:In Vitro Techniques; D007429:Intraocular Pressure / Q000187:drug effects*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D012995:Solubility; D013329:Structure-Activity Relationship; D013441:Sulfinic Acids / Q000737:chemistry / Q000494:pharmacology*; D013449:Sulfonamides / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D014018:Tissue Distribution; D014602:Uvea / Q000201:enzymology; D014867:Water
D002257:Carbonic Anhydrase Inhibitors; D007527:Isoenzymes; D011804:Quinolines; D013441:Sulfinic Acids; D013449:Sulfonamides; D014867:Water; C403544:8-quinolinesulfonyl chloride; D002256:Carbonic Anhydrases