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.
Copyright © 2014 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Glaucoma / drug therapy*
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Guinea Pigs
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Humans
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Inhibitory Concentration 50
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Models, Molecular
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Molecular Structure
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology
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Protein Kinase Inhibitors / therapeutic use*
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Pyrazines / chemical synthesis*
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Pyrazines / chemistry
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Pyrazines / pharmacology
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Pyrazines / therapeutic use*
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Pyridines / chemistry
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Pyridines / pharmacology
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Pyridines / therapeutic use
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rho-Associated Kinases / antagonists & inhibitors*
Substances
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Protein Kinase Inhibitors
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Pyrazines
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Pyridines
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Y-39983
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rho-Associated Kinases