Discovery and biological evaluation of potent, selective, orally bioavailable, pyrazine-based blockers of the Nav1.8 sodium channel with efficacy in a model of neuropathic pain

被引：30

作者：

Scanio, Marc J. C. ^{[1
]}

Shi, Lei ^{[1
]}

Drizin, Irene ^{[1
]}

Gregg, Robert J. ^{[1
]}

Atkinson, Robert N. ^{[2
]}

Thomas, James B. ^{[2
]}

Johnson, Matthew S. ^{[2
]}

Chapman, Mark L. ^{[2
]}

Liu, Dong ^{[2
]}

Krambis, Michael J. ^{[2
]}

Liu, Yi ^{[2
]}

Shieh, Char-Chang ^{[1
]}

Zhang, XuFeng ^{[1
]}

Simler, Gricelda H. ^{[1
]}

Joshi, Shailen ^{[1
]}

Honore, Prisca ^{[1
]}

Marsh, Kennan C. ^{[1
]}

Knox, Alison ^{[1
]}

Werness, Stephen ^{[2
]}

Antonio, Brett ^{[2
]}

Krafte, Douglas S. ^{[2
]}

Jarvis, Michael F. ^{[1
]}

Faltynek, Connie R. ^{[1
]}

Marron, Brian E. ^{[2
]}

Kort, Michael E. ^{[1
]}

机构：

[1] Abbott Labs, Global Pharmaceut Res & Dev, Abbott Pk, IL 60064 USA

[2] Icagen Inc, Durham, NC 27703 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2010年 / 18卷 / 22期

关键词：

Sodium channels; Na(v)1.8; PN3; Neuropathic pain; DERIVATIVES; NOMENCLATURE; EXPRESSION; A-803467; NEURONS; ASSAY;

D O I：

10.1016/j.bmc.2010.09.057

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Na(v)1.8 (also known as PN3) is a tetrodotoxin-resistant (TTx-r) voltage-gated sodium channel (VGSC) that is highly expressed on small diameter sensory neurons. It has been implicated in the pathophysiology of inflammatory and neuropathic pain, and we envisioned that selective blockade of Na(v)1.8 would be analgesic, while reducing adverse events typically associated with non-selective VGSC blocking therapeutic agents. Herein, we describe the preparation and characterization of a series of 6-aryl-2-pyrazinecarboxamides, which are potent blockers of the human Na(v)1.8 channel and also block TTx-r sodium currents in rat dorsal root ganglia (DRG) neurons. Selected derivatives display selectivity versus human Na(v)1.2. We further demonstrate that an example from this series is orally bioavailable and produces antinociceptive activity in vivo in a rodent model of neuropathic pain following oral administration. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：7816 / 7825

页数：10

共 10 条

[1] Discovery and pharmacological evaluation of potent, selective blockers of the Nav1.8 sodium channel with efficacy in models of neuropathic pain
Kort, Michael E.
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2009, 237
[2] Potent, selective pyrazine-based blockers of the Nav1.8 (PN3) sodium channel
Scanio, Marc J. C.
Shi, Lei
Kort, Michael E.
Drizin, Irene
Gregg, Robert J.
Thomas, James B.
Atkinson, Robert N.
Johnson, Matthew S.
Marron, Brian E.
Chapman, Mark L.
Liu, Dong
Krambis, Michael J.
Su, Xin
Shieh, Char-Chang
Zhang, XuFeng
Hernandez, Gricelda
Joshi, Shailen
Honore, Prisca
Marsh, Kennan C.
Knox, Alison
Werness, Stephen
Krafte, Douglas S.
Jarvis, Michael F.
Faltynek, Connie R.
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2007, 233 : 825 - 825
[3] MEDI 321-Potent, selective pyrazine-based blockers of the Nav1.8 (PN3) sodium channel
Wang, Guijun
Nie, Xiaoping
Hopkinson, Branden
Cheuk, Sherwin
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2007, 233 : 941 - 941
[4] Discovery and biological evaluation of 5-aryl-2-furfuramides, potent and selective blockers of the Nav1.8 sodium channel with efficacy in models of neuropathic and inflammatory pain
Kort, Michael E.
Drizin, Irene
Gregg, Robert J.
Scanio, Marc J. C.
Shi, Lei
Gross, Michael F.
Atkinson, Robert N.
Johnson, Matthew S.
Pacofsky, Gregory J.
Thomas, James B.
Carroll, William A.
Krambis, Michael J.
Liu, Dong
Shieh, Char-Chang
Zhang, XuFeng
Hernandez, Gricelda
Mikusa, Joseph P.
Zhong, Chengmin
Joshi, Shailen
Honore, Prisca
Roeloffs, Rosemarie
Marsh, Kennan C.
Murray, Bernard P.
Liu, Jinrong
Werness, Stephen
Faltynek, Connie R.
Krafte, Douglas S.
Jarvis, Michael F.
Chapman, Mark L.
Marron, Brian E.
JOURNAL OF MEDICINAL CHEMISTRY, 2008, 51 (03) : 407 - 416
[5] Subtype-selective Nav1.8 sodium channel blockers: Identification of potent, orally active nicotinamide derivatives
Kort, Michael E.
Atkinson, Robert N.
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Drizin, Irene
Johnson, Matthew S.
Secrest, Matthew A.
Gregg, Robert J.
Scanio, Marc J. C.
Shi, Lei
Hakeem, Ahmed H.
Matulenko, Mark A.
Chapman, Mark L.
Krambis, Michael J.
Liu, Dong
Shieh, Char-Chang
Zhang, XuFeng
Simler, Gricelda
Mikusa, Joseph P.
Zhong, Chengmin
Joshi, Shailen
Honore, Prisca
Roeloffs, Rosemarie
Werness, Stephen
Antonio, Brett
Marsh, Kennan C.
Faltynek, Connie R.
Krafte, Douglas S.
Jarvis, Michael F.
Marron, Brian E.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2010, 20 (22) : 6812 - 6815
[6] A-803467, a potent and selective Nav1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat
Jarvis, Michael F.
Honore, Prisca
Shieh, Char-Chang
Chapman, Mark
Joshi, Shailen
Zhang, Xu-Feng
Kort, Michael
Carroll, William
Marron, Brian
Atkinson, Robert
Thomas, James
Liu, Dong
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Liu, Yi
McGaraughty, Steve
Chu, Katharine
Roeloffs, Rosemarie
Zhong, Chengmin
Mikusa, Joseph P.
Hernandez, Gricelda
Gauvin, Donna
Wade, Carrie
Zhu, Chang
Pai, Madhavi
Scanio, Marc
Shi, Lei
Drizin, Irene
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Wagoner, P. Kay
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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2007, 104 (20) : 8520 - 8525
[7] Discovery of Hbw-3-80, a Potent, Bioavailable Sodium Channel Nav.1.8 Blocker for Pain
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ANNALS OF NEUROLOGY, 2021, 90 : S238 - S238
[8] 2-Aminopyridines as Potent and Selective Nav1.8 Inhibitors Exhibiting Efficacy in a Nonhuman Primate Pain Model
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ACS MEDICINAL CHEMISTRY LETTERS, 2024, 15 (06): : 917 - 923
[9] Alt0181-conotoxin SIIIA selective inhibition of Nav1.8 sodium channels in rat dorsal root ganglion neurons with efficacy in inflammatory pain model
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JOURNAL OF NEUROCHEMISTRY, 2006, 98 : 32 - 33
[10] Synthesis and biological evaluation of 1-(isoxazol-5-ylmethylaminoethyl)-4-phenyl tetrahydropyridine and piperidine derivatives as potent T-type calcium channel blockers with antinociceptive effect in a neuropathic pain model
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EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2014, 74 : 246 - 257

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