Phenyl isoxazole voltage-gated sodium channel blockers: Structure and activity relationship

doi:10.1016/j.bmcl.2011.05.041

Bioorganic & Medicinal Chemistry Letters

Volume 21, Issue 13, 1 July 2011, Pages 3871-3876

https://doi.org/10.1016/j.bmcl.2011.05.041 Get rights and content

Abstract

Blocking of certain sodium channels is considered to be an attractive mechanism to treat chronic pain conditions. Phenyl isoxazole carbamate 1 was identified as a potent and selective Na_V1.7 blocker. Structural analogues of 1, both carbamates, ureas and amides, were proven to be useful in establishing the structure–activity relationship and improving ADME related properties. Amide 24 showed a good overall in vitro profile, that translated well to rat in vivo PK.

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Acknowledgment

The authors wish to thank colleagues at Physical Chemistry Characterization Team for providing solubility data.

References and notes (10)

A.R. Harmer et al.
J. Pharm. Toxicol. Methods
(2008)
J.J. Cox et al.
Nature
(2006)
S. Ahmad et al.
Hum. Mol. Genet.
(2007)
Y. Yang et al.
J. Med. Genet.
(2004)
V. Zuliani et al.
Expert Opin. Ther. Patients
(2010)

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Bioorganic & Medicinal Chemistry Letters

Abstract

Graphical abstract

Section snippets

Acknowledgment

References and notes (10)

J. Pharm. Toxicol. Methods

Nature

Hum. Mol. Genet.

J. Med. Genet.

Expert Opin. Ther. Patients

Cited by (13)

The first synthesis of isoxazolo[3,4-c]pyridine-7-ones

Substituted 4-phenyl-2-aminoimidazoles and 4-phenyl-4,5-dihydro-2- aminoimidazoles as voltage-gated sodium channel modulators

Multiple machine learning methods aided virtual screening of Na<inf>V</inf>1.5 inhibitors

Bioactivation of isoxazole-containing bromodomain and extra-terminal domain (BET) inhibitors

GpTx-1 and [Ala<sup>5</sup>, Phe<sup>6</sup>, Leu<sup>26</sup>, Arg<sup>28</sup>]GpTx-1, two peptide Na<inf>V</inf>1.7 inhibitors: analgesic and tolerance properties at the spinal level

Recent trends in the discovery of small molecule blockers of sodium channels