In vivo optimization of 2,3-diaminopyrazine Rho Kinase inhibitors for the treatment of glaucoma

Bioorg Med Chem Lett. 2014 Apr 15;24(8):1875-9. doi: 10.1016/j.bmcl.2014.03.017. Epub 2014 Mar 19.

Abstract

A series of 2,3,6-pyrazine Rho Kinase inhibitors were optimized for in vivo activity for topical ocular dosing. Modifications of the 2-(piperazin-1-yl)pyrazine derivatives produced compounds with improved solubility and physicochemical properties. Modifications of the 6-pyrazine substituent led to improvements in in vitro potency. Compound 9 had the best in vitro and in vivo potency of EC50=260 nM with a 30% reduction of IOP in a non-human primate model at a dose of 0.33%.

Keywords: Glaucoma; IOP reduction; Pyrazine; Rho Kinase.

MeSH terms

  • Animals
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Glaucoma / drug therapy*
  • Guinea Pigs
  • Humans
  • Inhibitory Concentration 50
  • Models, Molecular
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • Pyrazines / chemical synthesis*
  • Pyrazines / chemistry
  • Pyrazines / pharmacology
  • Pyrazines / therapeutic use*
  • Pyridines / chemistry
  • Pyridines / pharmacology
  • Pyridines / therapeutic use
  • rho-Associated Kinases / antagonists & inhibitors*

Substances

  • Protein Kinase Inhibitors
  • Pyrazines
  • Pyridines
  • Y-39983
  • rho-Associated Kinases