IOP-lowering effect of isoquinoline-5-sulfonamide compounds in ocular normotensive monkeys

Bioorg Med Chem Lett. 2014 Feb 1;24(3):831-4. doi: 10.1016/j.bmcl.2013.12.085. Epub 2013 Dec 25.

Abstract

Rho-associated coiled coil-formed protein kinase (ROCK) inhibitors are under development as a new class of antiglaucoma agents. Based on the potent ROCK inhibitor H-1152, previously developed by us, we explored the possibility of related compounds as antiglaucoma agents and synthesized seven types of H-1152-inspired isoquinoline-5-sulfonamide compounds (H-0103-H-0107, H-1001, H-1005). Although all of these compounds potently inhibited ROCK (IC50=18-48 nM), only H-0104 and H-0106 exerted strong intraocular pressure (IOP)-lowering effects into the eyes of monkeys. These results suggested the possibility that there is no direct relationship between ROCK inhibition and IOP-lowering effects, indicating that the initial screening of compounds based on ROCK inhibitory activity may be an unsuitable strategy for developing antiglaucoma agents with potent IOP-lowering effects.

Keywords: Antiglaucoma agent; H-1152; Intraocular pressure (IOP)-lowering effect; Isoquinoline sulfonamide; ROCK inhibitor.

MeSH terms

  • Animals
  • Glaucoma* / drug therapy
  • Haplorhini
  • Inhibitory Concentration 50
  • Intraocular Pressure / drug effects*
  • Isoquinolines / chemistry
  • Isoquinolines / pharmacology*
  • Molecular Structure
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology*
  • rho-Associated Kinases / chemistry
  • rho-Associated Kinases / metabolism

Substances

  • Isoquinolines
  • Sulfonamides
  • isoquinoline-5-sulfonamide
  • rho-Associated Kinases