CARBONIC-ANHYDRASE INHIBITORS - PART 53 - SYNTHESIS OF SUBSTITUTED-PYRIDINIUM DERIVATIVES OF AROMATIC SULFONAMIDES - THE FIRST NON-POLYMERIC MEMBRANE-IMPERMEABLE INHIBITORS WITH SELECTIVITY FOR ISOZYME-IV
Ct. Supuran et al., CARBONIC-ANHYDRASE INHIBITORS - PART 53 - SYNTHESIS OF SUBSTITUTED-PYRIDINIUM DERIVATIVES OF AROMATIC SULFONAMIDES - THE FIRST NON-POLYMERIC MEMBRANE-IMPERMEABLE INHIBITORS WITH SELECTIVITY FOR ISOZYME-IV, European journal of medicinal chemistry, 33(7-8), 1998, pp. 577-594
Reaction of three aromatic sulfonamides containing a free amino group,
i.e., sulfanilamide, homosulfanilamide and 4-(2-aminoethyl)-benzenesu
lfonamide with di-, tri- or tetra-substituted pyrylium salts afforded
three series of cationic sulfonamides, containing a large variety of m
oieties substituting the pyridinium ring. The new derivatives were ass
ayed as inhibitors of three carbonic anhydrase (CA) isozymes, CA I, II
(cytosolic forms) and IV (membrane-bound form). Efficient inhibition
was observed against all three isozymes, but due to the cationic natur
e of these inhibitors, in vivo and ex vivo experiments showed that onl
y CA IV is selectively inhibited to a high degree, without affecting t
he cytosolic isozymes, present in appreciable concentrations in the ex
perimental model used. This is the first example of selective in vivo
inhibition of only one physiologically relevant CA isozyme with non-po
lymeric inhibitors and might lead to more selective drugs from this cl
ass of pharmacological agents. (C) Elsevier, Paris.