Carbonic anhydrase inhibitors. The mitochondrial isozyme VB as a new target for sulfonamide and sulfamate inhibitors

J Med Chem. 2005 Dec 1;48(24):7860-6. doi: 10.1021/jm050483n.


A lately discovered carbonic anhydrase (hCA, EC, the mitochondrial hCA VB, was cloned, expressed, and purified. Kinetic parameters proved it to be 3.37 times more effective than hCA VA as a catalyst for the physiological reaction, with kcat = 9.5 x 10(5) s(-1) and kcat/K(M) = 9.8 x 10(7) M(-1) s(-1), being second only to hCA II among the 16 isoforms presently known in humans. We investigated the inhibition of hCA VB with a library of sulfonamides/sulfamates, some of which are clinically used compounds. Benzenesulfonamides were ineffective inhibitors, whereas derivatives bearing 4-amino, 4-hydrazino, 4-methyl, 4-carboxy moieties or halogenated sulfanilamides were more effective (Ki's of 1.56-4.3 microM). Among the 10 clinically used compounds, acetazolamide, benzolamide, topiramate, and indisulam showed effective inhibitory activity (Ki's of 18-62 nM). Three compounds showed better activity against hCA VB over hCA II, among which were sulpiride and ethoxzolamide, which were 2 times more effective inhibitors of the mitochondrial over the cytosolic isozyme. hCA VB is a druggable target and some of its inhibitors may lead to the development of novel antiobesity therapies.

Publication types

  • Comparative Study

MeSH terms

  • Amino Acid Sequence
  • Carbonic Anhydrase Inhibitors / chemistry*
  • Carbonic Anhydrase V / chemistry*
  • Carbonic Anhydrase V / genetics
  • Carbonic Anhydrase V / isolation & purification
  • Catalysis
  • Cloning, Molecular
  • Humans
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / chemistry
  • Kinetics
  • Mitochondria / enzymology*
  • Molecular Sequence Data
  • Structure-Activity Relationship
  • Sulfonamides / chemistry*
  • Sulfonic Acids / chemistry*


  • Carbonic Anhydrase Inhibitors
  • Isoenzymes
  • Sulfonamides
  • Sulfonic Acids
  • sulfamic acid
  • Carbonic Anhydrase V