Reaction of several aromatic/heterocyclic sulfonamides containing a free amino, imino, hydrazino, or hydroxyl group, with 2, 3-pyridinedicarboxylic anhydride or 2,6-pyridinedicarboxylic acid in the presence of carbodiimide derivatives, afforded two series of water-soluble (as hydrochloride, triflate, or carboxylate 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 and IV (in nanomolar range), the two isozymes known to play a critical role in aqueous humor secretion within the ciliary processes of the eye. Some of the best inhibitors synthesized were applied as 2% water solutions directly into the eye of normotensive and glaucomatous albino rabbits. Very 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 topical application, such as dorzolamide, are derivatives of this ring system. To prove that the tail (in this case the pyridinecarboxylic moieties) conferring water solubility to a sulfonamide CA inhibitor is more important than the ring to which the sulfonamido group is grafted, we also prepared dorzolamide derivatives incorporating such moieties. These new compounds possess good water solubility as hydrochloride or carboxylate salts, balanced by a relatively modest lipid solubility. They are strong CA II inhibitors and are able to lower IOP in experimental animals more than the parent derivatives. Our conclusion is that the tail conferring water solubility to such an enzyme inhibitor is more important for topical activity as an antiglaucoma drug, than the heterocyclic/aromatic ring to which the sulfonamido moiety is grafted.
Reaction of perfluoroalkyl/arylsulfonyl chlorides or perfluoroalkyl/arylcarbonyl chlorides with aromatic/heterocyclic sulfonamides possessing a free amino/imino/hydrazino/hydroxy group afforded compounds with the general formula C(x)()F(y)()Z-A-SO(2)NH(2), where Z = SO(2)NH, SO(3), CONH, or CO(2) and A = aromatic/heterocyclic moiety. The sulfonyl chlorides used in synthesis included: CF(3)SO(2)Cl, n-C(4)F(9)SO(2)Cl, n-C(8)F(17)SO(2)Cl, and C(6)F(5)SO(2)Cl, whereas the acyl chlorides were C(8)F(17)COCl and C(6)F(5)COCl. A total of 25 different sulfonamides have been derivatized by means of the above-mentioned perfluorosulfonyl/acyl halides. These new series of sulfonamides showed strong affinities toward isozymes I, II, and IV of carbonic anhydrase (CA). For a given sulfonamide derivatized by the above procedures, inhibitory power was greater for the alkyl/arylsulfonylated compounds, as compared to the corresponding perfluoroalkyl/arylcarbonylated ones. In vitro inhibitory activity generally increased with the number of carbon atoms in the molecule of the acylating/sulfonylating agent, with a maximum for the perfluorophenylsulfonylated and perfluorobenzoylated derivatives. Some of the prepared CA inhibitors displayed very good water solubility (in the range of 2%) and strongly lowered intraocular pressure (IOP) when applied topically, directly into the normotensive/glaucomatous rabbit eye, as 2% water solutions. The good water solubility of these new classes of CA inhibitors, correlated with the neutral pH of their solutions used in the ophthalmologic applications, makes them attractive candidates for developing novel types of antiglaucoma drugs devoid of unpleasant ocular side effects.
Reaction of 26 aromatic/heterocyclic sulfonamides containing amino, imino, hydrazino, or hydroxyl groups with Boc-Gly, Boc-Sar, TrS-Crt, or Boc-Gly-Gly (Sar = sarcosine, N-Me-Gly; Crt = creatine, N-amidinosarcosine; TrS = tritylsulfenyl; Boc = tert-butoxycarbonyl) in the presence of carbodiimide derivatives afforded after removal of the protecting groups a series of water-soluble compounds (as salts of strong acids, such as hydrochloric, trifluoroacetic, or trifluoromethanesulfonic). 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 and especially against CA II and IV (in the nanomolar range), the two isozymes known to play a critical role in aqueous humor secretion within the ciliary processes of the eye. Some of the best inhibitors synthesized were applied as 2% water solutions into the eye of normotensive or glaucomatous albino rabbits, when strong and long-lasting intraocular pressure (IOP) lowering was observed with many of them. Thus, the aminoacyl/dipeptidyl tail conferring water solubility to these sulfonamide CA inhibitors coupled with strong enzyme inhibitory properties and balanced lipid solubility seem to be the key factors for obtaining compounds with effective topical antiglaucoma activity.
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