Monothiocarbamates Strongly Inhibit Carbonic Anhydrases in Vitro and Possess Intraocular Pressure Lowering Activity in an Animal Model of Glaucoma

J Med Chem. 2016 Jun 23;59(12):5857-67. doi: 10.1021/acs.jmedchem.6b00462. Epub 2016 Jun 13.

Abstract

A series of monothiocarbamates (MTCs) were prepared from primary/secondary amines and COS as potential carbonic anhydrase (CA, EC 4.2.1.1) inhibitors, using the dithiocarbamates, the xanthates, and the trithiocarbonates as lead compounds. The MTCs effectively inhibited the pharmacologically relevant human (h) hCAs isoforms I, II, IX, and XII in vitro and showed KIs spanning between the low and medium nanomolar range. By means of a computational study, the MTC moiety binding mode on the CAs was explained. Furthermore, a selection of MTCs were evaluated in a normotensive glaucoma rabbit model for their intraocular pressure (IOP) lowering effects and showed interesting activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carbonic Anhydrase Inhibitors / chemical synthesis
  • Carbonic Anhydrase Inhibitors / chemistry
  • Carbonic Anhydrase Inhibitors / pharmacology*
  • Carbonic Anhydrases / metabolism*
  • Disease Models, Animal*
  • Dose-Response Relationship, Drug
  • Glaucoma / drug therapy*
  • Humans
  • Intraocular Pressure / drug effects*
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / metabolism
  • Models, Molecular
  • Molecular Structure
  • Rabbits
  • Structure-Activity Relationship

Substances

  • Carbonic Anhydrase Inhibitors
  • Isoenzymes
  • Carbonic Anhydrases