N-aryl-N'-ureido-O-sulfamates: Potent and selective inhibitors of the human Carbonic Anhydrase VII isoform with neuropathic pain relieving properties

Bioorg Chem. 2019 Aug:89:103033. doi: 10.1016/j.bioorg.2019.103033. Epub 2019 Jun 6.

Abstract

Herein we report for the first time an efficient synthetic procedure for the preparation of N-aryl-N'-ureido-O-sulfamates (AUSs) as a new class of Carbonic Anhydrase Inhibitors (CAIs). The compounds were tested for the inhibition of several human (h) Carbonic Anhydrase (CA; EC 4.2.1.1) isoforms. Interesting inhibition activity and high selectivity against CA VII and XII versus CA I and II, with KIs in the low nanomolar range, were observed. Molecular modeling studies allowed us to decipher the structural features underpinning the selective inhibitory profile of AUSs towards isoforms CAs VII and XII. A selection of sulfamates showed promising neuropathic pain modulating effects in an in vivo animal model of oxaliplatin induced pain.

Keywords: Carbonic Anhydrase; Carbonic Anhydrase Inhibitors; N-aryl-N’-ureido-O-sulfamates; Neuropathic pain.

MeSH terms

  • Animals
  • Carbonic Anhydrase Inhibitors / chemical synthesis
  • Carbonic Anhydrase Inhibitors / chemistry
  • Carbonic Anhydrase Inhibitors / pharmacology*
  • Carbonic Anhydrases / metabolism*
  • Dose-Response Relationship, Drug
  • Drug Design
  • Humans
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / metabolism
  • Male
  • Mice
  • Models, Molecular
  • Molecular Structure
  • Neuralgia / chemically induced
  • Neuralgia / drug therapy*
  • Neuralgia / pathology
  • Oxaliplatin
  • Pain Measurement*
  • Phenylurea Compounds / chemical synthesis
  • Phenylurea Compounds / chemistry
  • Phenylurea Compounds / pharmacology*
  • Structure-Activity Relationship

Substances

  • Carbonic Anhydrase Inhibitors
  • Isoenzymes
  • Phenylurea Compounds
  • Oxaliplatin
  • Carbonic Anhydrases
  • carbonic anhydrase VI