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

Hwang Hsing Chen, Abdelmoulah Namil, Bryon Severns, Jennifer Ward, Curtis Kelly, Colene Drace, Marsha A. McLaughlin, Shenouda Yacoub, Byron Li, Raj Patil, Naj Sharif, Mark R. Hellberg, Andrew Rusinko, Iok Hou Pang, Keith D. Combrink

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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%.

Original languageEnglish
Pages (from-to)1875-1879
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume24
Issue number8
DOIs
StatePublished - 15 Apr 2014

Keywords

  • Glaucoma
  • IOP reduction
  • Pyrazine
  • Rho Kinase

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    Chen, H. H., Namil, A., Severns, B., Ward, J., Kelly, C., Drace, C., McLaughlin, M. A., Yacoub, S., Li, B., Patil, R., Sharif, N., Hellberg, M. R., Rusinko, A., Pang, I. H., & Combrink, K. D. (2014). In vivo optimization of 2,3-diaminopyrazine Rho Kinase inhibitors for the treatment of glaucoma. Bioorganic and Medicinal Chemistry Letters, 24(8), 1875-1879. https://doi.org/10.1016/j.bmcl.2014.03.017