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?

Citation
J. Borras et al., 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?, BIO MED CH, 7(11), 1999, pp. 2397-2406
Citations number
59
Categorie Soggetti
Chemistry & Analysis
Journal title
BIOORGANIC & MEDICINAL CHEMISTRY
ISSN journal
09680896 → ACNP
Volume
7
Issue
11
Year of publication
1999
Pages
2397 - 2406
Database
ISI
SICI code
0968-0896(199911)7:11<2397:CAISOW>2.0.ZU;2-G
Abstract
Reaction of 20 aromatic/heterocyclic sulfonamides containing a free amino, imino, hydrazino or hydroxyl group, with 8-quinoline-sulfonyl chloride affo rded a series of water-soluble las hydrochloride or triflate salts) compoun ds. The new derivatives were assayed as inhibitors of the zinc enzyme carbo nic anhydrase (CA), and more precisely of three of its isozymes, CA I, II ( cytosolic forms) and IV Imembrane-bound form), involved in important physio logical processes. Efficient inhibition was observed against all three isoz ymes, but especially against CA II tin nanomolar range), which is the isozy me known to play a critical role in aqueous humor secretion within the cili ary processes of the eye. Some of the best inhibitors synthesized were topi cally applied as 2% water solutions onto the eye of normotensive and glauco matous albino rabbits, when strong and long-lasting intraocular pressure (I OP) lowering was observed with many of them. This result prompted us to rea nalyze the synthetic work done by other groups for the design of water solu ble, topically effective antiglaucoma sulfonamides. According to these rese archers, the IOP lowering effect is due to the intrinsic nature of the spec ific 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 derivativ es of this ring system. In order to prove that the tail tin 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 i s grafted, we also prepared a dorzolamide derivative to which the 8-quinoli ne-sulfonyl moiety was attached, This new compound is quite water soluble a s hydrochloride salt, behaves as a strong CA II inhibitor, and fared better than the parent molecule in lowering IOP in experimental animals. Thus, th e tail conferring water solubility to such an enzyme inhibitor is more impo rtant for its topical activity as antiglaucoma drug than the heterocyclic/a romatic ring to which the sulfonamido moiety is grafted. (C) 1999 Elsevier Science Ltd. All rights reserved.