Carbonic anhydrase inhibitors. Phenacetyl-, pyridylacetyl- and thienylacetyl-substituted aromatic sulfonamides act as potent and selective isoform VII inhibitors

Bioorg Med Chem Lett. 2009 Jun 15;19(12):3170-3. doi: 10.1016/j.bmcl.2009.04.123. Epub 2009 May 3.

Abstract

A series of aromatic/heterocyclic sulfonamides incorporating phenyl(alkyl), halogenosubstituted-phenyl- or 1,3,4-thiadiazole-sulfonamide moieties and thienylacetamido; phenacetamido- and pyridinylacetamido tails were prepared and assayed as inhibitors of cytosolic human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms hCA I, II and VII. The new compounds showed moderate inhibition of the two ubiquitous isoforms I and II (K(I)s of 50-390 nM) and excellent inhibitory activity against the brain associated hCA VII (K(I)s in the range of 4.7-8.5 nM). Isoform VII highly selective inhibitors are being detected for the first time, with selectivity ratios for inhibiting CA VII over CA II of 11-75, and for inhibiting CA VII over CA I of 10-49, which may be useful for understanding the role of CA VII in epileptogenesis and other physiologic processes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Brain Chemistry
  • Carbonic Anhydrase Inhibitors / chemical synthesis
  • Carbonic Anhydrase Inhibitors / chemistry*
  • Carbonic Anhydrase Inhibitors / pharmacology
  • Carbonic Anhydrases / drug effects*
  • Humans
  • Hydrocarbons, Aromatic
  • Protein Isoforms
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis
  • Sulfonamides / chemistry*
  • Sulfonamides / pharmacology

Substances

  • Carbonic Anhydrase Inhibitors
  • Hydrocarbons, Aromatic
  • Protein Isoforms
  • Sulfonamides
  • Carbonic Anhydrases
  • carbonic anhydrase VI