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

doi:10.1016/j.bmcl.2014.03.017

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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11 Scopus citations

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 language	English
Pages (from-to)	1875-1879
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	24
Issue number	8
DOIs	https://doi.org/10.1016/j.bmcl.2014.03.017
State	Published - 15 Apr 2014

Keywords

Glaucoma
IOP reduction
Pyrazine
Rho Kinase

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10.1016/j.bmcl.2014.03.017

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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

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

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",

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

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doi = "10.1016/j.bmcl.2014.03.017",

language = "English",

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Chen, HH, Namil, A, Severns, B, Ward, J, Kelly, C, Drace, C, McLaughlin, MA, Yacoub, S, Li, B, Patil, R, Sharif, N, Hellberg, MR, Rusinko, A, Pang, IH & Combrink, KD 2014, 'In vivo optimization of 2,3-diaminopyrazine Rho Kinase inhibitors for the treatment of glaucoma', Bioorganic and Medicinal Chemistry Letters, vol. 24, no. 8, pp. 1875-1879. https://doi.org/10.1016/j.bmcl.2014.03.017

TY - JOUR

T1 - In vivo optimization of 2,3-diaminopyrazine Rho Kinase inhibitors for the treatment of glaucoma

AU - Chen, Hwang Hsing

AU - Namil, Abdelmoulah

AU - Severns, Bryon

AU - Ward, Jennifer

AU - Kelly, Curtis

AU - Drace, Colene

AU - McLaughlin, Marsha A.

AU - Yacoub, Shenouda

AU - Li, Byron

AU - Patil, Raj

AU - Sharif, Naj

AU - Hellberg, Mark R.

AU - Rusinko, Andrew

AU - Pang, Iok Hou

AU - Combrink, Keith D.

PY - 2014/4/15

Y1 - 2014/4/15

N2 - 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%.

AB - 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%.

KW - Glaucoma

KW - IOP reduction

KW - Pyrazine

KW - Rho Kinase

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AN - SCOPUS:84897520919

SN - 0960-894X

VL - 24

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EP - 1879

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 8

ER -

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

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