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?
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
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.