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

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

Author information

1
Alcon Laboratories Inc, A Division of Novartis, 6201 South Freeway, Fort Worth, TX 76134, USA.
2
Alcon Laboratories Inc, A Division of Novartis, 6201 South Freeway, Fort Worth, TX 76134, USA. Electronic address: kdcom1@yahoo.com.

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

PMID:
24684843
DOI:
10.1016/j.bmcl.2014.03.017
[Indexed for MEDLINE]

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