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In vivo optimization of 2,3-diaminopyrazine Rho Kinase inhibitors for the treatment of glaucoma.
Hwang-Hsing Chen
1 ,
Abdelmoulah Namil
1 ,
Bryon Severns
1 ,
Jennifer Ward
1 ,
Curtis Kelly
1 ,
Colene Drace
1 ,
Marsha A McLaughlin
1 ,
Shenouda Yacoub
1 ,
Byron Li
1 ,
Raj Patil
1 ,
Naj Sharif
1 ,
Mark R Hellberg
1 ,
Andrew Rusinko
1 ,
Iok-Hou Pang
1 ,
Keith D Combrink
2
Apr 15 2014
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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%.