Carbonic Anhydrase Inhibitors:  Synthesis of Water-Soluble, Aminoacyl/Dipeptidyl Sulfonamides Possessing Long-Lasting Intraocular Pressure-Lowering Properties via the Topical Route

Abstract

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.

Carbonic anhydrase inhibitors

“…This approach has been developed in our laboratory [46][47][48][49][50][51][52][53][54][55][56][57][58][59][60] and consists in using well-known aromatic/ heterocyclic sulfonamide scaffolds (of type A-Y) to which tails that will induce water solubility are attached at the amino, hydroxy, imino, or hydrazino moieties contained in the precursor sulfonamides A-Y.…”

“…[46][47][48][49][50][51][52][53][54][55][56][57][58][59][60] Tails that were introduced in the molecules of such new CAIs contained either moieties protonable at endocyclic nitrogen atoms (such as pyridine-or quinoline rings 30-35), or at amino groups belonging to amino acids and some of their derivatives (such as glycine, b-alanine, GABA, sarcosine, creatine, diethylenetriaminopentaacetic acid (dtpa), or glycyl-glycine moieties of types 36-42), as well as perfluoroalkyl/aryl moieties (which are not protonable at pH values in the neutral range, of types [43][44][45][46][47][48]. The water solubility of the first type of such derivatives is assured by formation of salts with hydrochloric, trifluoroacetic or triflic acid, or by formation of sodium salts, for the derivatives possessing carboxylic acid moieties (tails of types 34 or 41).…”

“…For instance, 30C should be the isonicotinoylamido derivative of sulfanilamide, 36M the glycinamido derivative of 5-amino-1,3,4-thiadiazole-2-sulfonamide, etc. [46][47][48][49][50][51][52][53][54][55][56][57][58][59][60] The main advantages of this over the ring approach are that the first is much more simple than the second, and it allows a parallel type synthesis easily, so that a large number of different derivatives may be prepared, and their physico-chemical properties modulated in such a way as to assure the desired pharmacological properties. By choosing different tails, it is possible to attain the much desired water solubility of these CAIs (as salts of acids or bases) at pH values in the neighborhood of neutrality, avoiding thus the irritation problems observed with the strongly acidic dorzolamide solutions.…”

“…Such solutions were never irritating for the eye of experimental animals. [46][47][48][49][50][51][52][53][54][55][56][57][58][59][60] Sulfonamides obtained by incorporating pyridine-carboxamido-or quinoline-sulfonamido tails (of types 30-35) into the scaffolds A-Y were in many cases nanomolar inhibitors of isozymes hCA II and bCA IV, [46][47][48][49][50][51][52] possessed good water solubility in the range of 1.5-2%, and the pH of their solutions used for in vivo experiments was in the range of 6.5-7.5. Many of these compounds were very effective IOP lowering agents in normotensive and glaucomatous albino rabbits, with potencies 2-3 times superior to dorzolamide.…”

“…Many of these compounds were very effective IOP lowering agents in normotensive and glaucomatous albino rabbits, with potencies 2-3 times superior to dorzolamide. [46][47][48][49][50][51][52] New derivatives prepared by the tail approach, incorporating amino acyl-, oligopeptidyl-, or polyaminopolycarboxyl-moieties (of types 36-42) were again potent inhibitors of isozymes CA I, CA II, and CA IV, and could be formulated in water solutions in the concentration range of 2-2.5%, at almost neutral pH values (pH 6-7). [53][54][55]59 A special case of this approach was constituted by the perfluoroalkyl-/aryl-containing derivatives, which incorporated tails 43-48.…”