Bioavailable pyrrolo-benzo-1,4-diazines as Nav1.7 sodium channel blockers for the treatment of pain

被引：12

作者：

Yang, Shu-Wei ^{[1
]}

Ho, Ginny D. ^{[1
]}

Tulshian, Deen ^{[1
]}

Bercovici, Ana ^{[1
]}

Tan, Zheng ^{[1
]}

Hanisak, Jennifer ^{[1
]}

Brumfield, Stephanie ^{[1
]}

Matasi, Julius ^{[1
]}

Sun, Xianfeng ^{[2
]}

Sakwa, Samuel A. ^{[2
]}

Herr, R. Jason ^{[2
]}

Zhou, Xiaoping ^{[3
]}

Bridal, Terry ^{[4
]}

Urban, Mark ^{[5
]}

Vivian, Jeffrey ^{[5
]}

Rindgen, Diane ^{[6
]}

Sorota, Steve ^{[4
]}

机构：

[1] Merck Res Lab, Discovery Chem, Kenilworth, NJ 07033 USA

[2] Albany Mol Res Inc, Dept Med Chem, Albany, NY 12203 USA

[3] Merck Res Lab, In Vivo Pharmacol Grp, Kenilworth, NJ 07033 USA

[4] Merck Res Lab, Cardiorenal Grp, Kenilworth, NJ 07033 USA

[5] Merck Res Lab, Neurosci, Kenilworth, NJ 07033 USA

[6] Merck Res Lab, Pharmacokinet Pharmacodynam & Drug Metab, Kenilworth, NJ 07033 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2014年 / 24卷 / 21期

关键词：

Na(v)1.7; Na(v)1.5; Sodium channel; Pain; GENES; EXPRESSION; MUTATION; NEURONS;

D O I：

10.1016/j.bmcl.2014.09.038

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of pyrrolo-benzo-1,4-diazine analogs have been synthesized to improve the profile of the previous lead compound 1. The syntheses, structure-activity relationships, and selected pharmacokinetic data of these analogs are described. The optimization efforts allowed the identification of 33, a quinoline amide exhibiting potent Na(v)1.7 inhibitory activity and moderate selectivity over Na(v)1.5. Compound 33 displayed anti-nociceptive oral efficacy in a rat CFA inflammatory pain model at 100 mpk and in a rat spinal nerve ligation neuropathic pain model with an EC50 75 mu M. (C) 2014 Elsevier Ltd. All rights reserved.

引用

页码：4958 / 4962

页数：5

共 47 条

[1] Discovery of pyrrolo-benzo-1,4-diazines as potent Nav1.7 sodium channel blockers
Ho, Ginny D.
Tulshian, Deen
Bercovici, Ana
Tan, Zheng
Hanisak, Jennifer
Brumfield, Stephanie
Matasi, Julius
Heap, Charles R.
Earley, William G.
Courneya, Brandy
Herr, R. Jason
Zhou, Xiaoping
Bridal, Terry
Rindgen, Diane
Sorota, Steve
Yang, Shu-Wei
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2014, 24 (17) : 4110 - 4113
[2] Discovery of pyrrolo-benzo-1,4-diazines as potent Nav1.7 sodium channel blockers
Ho, Ginny D.
Tulshian, Deen
Bercovici, Ana
Tan, Zheng
Hanisak, Jennifer
Cooke, Stephanie
Matasi, Julius
Heap, Charles R.
Earley, William G.
Courneya, Brandy
Zhou, Xiaoping
Bridal, Terry
Rindgen, Diane
Hyde, Lynn
Cohen-Williams, Mary
Sorota, Steve
Yang, Shu-Wei
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2014, 248
[3] Substituted Indazoles as Nav1.7 Blockers for the Treatment of Pain
Frost, Jennifer M.
DeGoey, David A.
Shi, Lei
Gum, Rebecca J.
Fricano, Meagan M.
Lundgaard, Greta L.
El-Kouhen, Odile F.
Hsieh, Gin C.
Neelands, Torben
Matulenko, Mark A.
Daanen, Jerome F.
Pai, Madhavi
Ghoreishi-Haack, Nayereh
Zhan, Cenchen
Zhang, Xu-Feng
Kort, Michael E.
JOURNAL OF MEDICINAL CHEMISTRY, 2016, 59 (07) : 3373 - 3391
[4] Familial pain syndromes from mutations of the Nav1.7 sodium channel
Fischer, Tanya Z.
Waxman, Stephen G.
YEAR IN NEUROLOGY 2, 2010, 1184 : 196 - 207
[5] Engineering Highly Potent and Selective Microproteins against Nav1.7 Sodium Channel for Treatment of Pain
Shcherbatko, Anatoly
Rossi, Andrea
Foletti, Davide
Zhu, Guoyun
Bogin, Oren
Casas, Meritxell Galindo
Rickert, Mathias
Hasa-Moreno, Adela
Bartsevich, Victor
Crameri, Andreas
Steiner, Alexander R.
Henningsen, Robert
Gill, Avinash
Pons, Jaume
Shelton, David L.
Rajpal, Arvind
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JOURNAL OF BIOLOGICAL CHEMISTRY, 2016, 291 (27) : 13974 - 13986
[6] Mechanism of inhibition by chlorpromazine of the human pain threshold sodium channel, Nav1.7
Lee, Su-Jin
Kim, Dong-Hyun
Hahn, Sang June
Waxman, Stephen G.
Choi, Jin-Sung
NEUROSCIENCE LETTERS, 2017, 639 : 1 - 7
[7] Evolution of ProTx-II Peptide Selective Blockers of Nav1.7 Channel as Potential Therapeutics for the Treatment of Pain
Colarusso, Stefania
De Simone, Daniele
Frattarelli, Tommaso
Iaccarino, Roberto
Pasquini, Nicolo' Maria
Magotti, Paola
Palani, Anandan
Sun, Chengzao
Adams, Gregory L.
Tellers, David
Bianchi, Elisabetta
JOURNAL OF PEPTIDE SCIENCE, 2022, 28
[8] High-Throughput Screening of Nav1.7 Sodium Channel Blockers in an Automated Patch Clamp Assay
Li, Tianbo
Lu, Gang
Chernov-Rogan, Tania
Chen, Jun
BIOPHYSICAL JOURNAL, 2017, 112 (03) : 240A - 240A
[9] Uncoupling sodium channel dimers restores the phenotype of a pain-linked Nav1.7 channel mutation
Ruehlmann, Annika H.
Koerner, Jannis
Hausmann, Ralf
Bebrivenski, Nikolay
Neuhof, Christian
Detro-Dassen, Silvia
Hautvast, Petra
Benasolo, Carene A.
Meents, Jannis
Machtens, Jan-Philipp
Schmalzing, Guenther
Lampert, Angelika
BRITISH JOURNAL OF PHARMACOLOGY, 2020, 177 (19) : 4481 - 4496
[10] Endogenous opioids contribute to insensitivity to pain in humans and mice lacking sodium channel Nav1.7
Minett, Michael S.
Pereira, Vanessa
Sikandar, Shafaq
Matsuyama, Ayako
Lolignier, Stephane
Kanellopoulos, Alexandros H.
Mancini, Flavia
Iannetti, Gian D.
Bogdanov, Yury D.
Santana-Varela, Sonia
Millet, Queensta
Baskozos, Giorgios
MacAllister, Raymond
Cox, James J.
Zhao, Jing
Wood, John N.
NATURE COMMUNICATIONS, 2015, 6

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