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

Macsári, István; Sandberg, Lars; Besidski, Yevgeni; Gravenfors, Ylva; Ginman, Tobias; Bylund, Johan; Bueters, Tjerk; Eriksson, Anders; Lund, Per-Eric; Venyike, Elisabet; Arvidsson, Per I.

doi:10.1016/j.bmcl.2011.05.041

Cited by 11 publications

(17 citation statements)

References 7 publications

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“…Currently, Na V 1.7 inhibitors are classified into small molecular inhibitors and peptide inhibitors according to their chemical structure. Several compounds, including benzazepinones, amino‐thiazoles, amino‐pyridines and isoxazoles, were found to be Na V 1.7 blockers (Hoyt et al ., ; Macsari et al ., ). CNV‐1014802 (GSK‐1014802, BIIB074), PF‐04856264 and PF‐05089771 were also found to be selective inhibitors of Na V 1.7 channels in previous studies (McCormack et al ., ; Alexandrou et al ., ).…”

Section: Introductionmentioning

confidence: 99%

GpTx‐1 and [Ala⁵, Phe⁶, Leu²⁶, Arg²⁸]GpTx‐1, two peptide Na_V1.7 inhibitors: analgesic and tolerance properties at the spinal level

Chen

Shi

et al. 2018

British J Pharmacology

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Section: Introductionmentioning

confidence: 99%

GpTx‐1 and [Ala⁵, Phe⁶, Leu²⁶, Arg²⁸]GpTx‐1, two peptide Na_V1.7 inhibitors: analgesic and tolerance properties at the spinal level

Chen

Shi

et al. 2018

British J Pharmacology

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“…Xenon Pharmaceuticals reported two candidates in clinical development which, according to the company's website, "specifically target the sodium channels such as Na v 1.7", even though selectivity data for Na v 1.7 over other subtypes have not been yet released in the public domain. Aminopyrazines 2012 Na v 1.7 - [257] Aminopyrimidinones 2012 Na v 1.7 - [258] Aminotriazines 2011 Na v 1.7 Formalin model of pain (rats) [255] XEN907, spirooxindole 2011 Na v 1.7 - [362] Phenylisoxazoles 2011 Na v 1.7 - [363] Z123212 2011 Common strategy to identify voltage protocols for use-and statedependency assays in manual or automated whole-cell patch-clamp electrophysiology for any member of the Na v 1 channel family.…”

Section: Individual Subtypes As Drug Targetsmentioning

confidence: 99%

Advances in Targeting Voltage‐Gated Sodium Channels with Small Molecules

Nardi¹,

Damann²,

Hertrampf³

et al. 2012

ChemMedChem

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Blockade of voltage-gated sodium channels (VGSCs) has been used successfully in the clinic to enable control of pathological firing patterns that occur in conditions as diverse as chronic pain, epilepsy, and arrhythmias. Herein we review the state of the art in marketed sodium channel inhibitors, including a brief compendium of their binding sites and of the cellular and molecular biology of sodium channels. Despite the preferential action of this drug class toward over-excited cells, which significantly limits potential undesired side effects on other cells, the need to develop a second generation of sodium channel inhibitors to overcome their critical clinical shortcomings is apparent. Current approaches in drug discovery to deliver novel and truly innovative sodium channel inhibitors is next presented by surveying the most recent medicinal chemistry breakthroughs in the field of small molecules and developments in automated patch-clamp platforms. Various strategies aimed at identifying small molecules that target either particular isoforms of sodium channels involved in specific diseases or anomalous sodium channel currents, irrespective of the isoform by which they have been generated, are critically discussed and revised.

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“…Test compounds originated from the compound collection of AstraZeneca R&D, and the synthesis of such derivatives has been described by Macsari et al (2011), with the exception of the isomeric phenyl 5Ј-methylisoxazole analogs (compounds 18 and 19) that are described in the supplemental data (Supplemental Figs. 1 and 2).…”

Section: Methodsmentioning

confidence: 99%

“…Also N-substitution of the 4Ј-nitrogen with a methyl group (15), blocked the GSH adduct formation. However, these structural modifications also led to less potent compounds (Macsari et al, 2011). Therefore, we turned our attention to carboxamides, derivatives where the nitrogen is replaced by a carbon (compounds 16 and 17).…”

Section: Inmentioning

confidence: 99%

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Novel Bioactivation Mechanism of Reactive Metabolite Formation from Phenyl Methyl-Isoxazoles

et al. 2012

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ABSTRACT:Recently, we described a series of phenyl methyl-isoxazole derivatives as novel, potent, and selective inhibitors of the voltage-gated sodium channel type 1.7 (Bioorg Med Chem Lett 21:3871-3876, 2011). The lead compound, 2-chloro-6-fluorobenzyl [3-(2,6-dichlorophenyl)-5-methylisoxazol-4-yl]carbamate, showed unprecedented GSH and cysteine reactivity associated with NADPH-dependent metabolism in trapping studies using human liver microsomes. Additional trapping experiments with close analogs and mass spectra and NMR analyses suggested that the conjugates were attached directly to the 5-methyl on the isoxazole moiety. We propose a mechanism of bioactivation via an initial oxidation of the 5-methyl generating a stabilized enimine intermediate and a subsequent GSH attack on the 5-methylene. Efforts to ameliorate reactive metabolite generation were undertaken to minimize the potential risk of toxicity. Formation of reactive metabolites could be significantly reduced or prevented by removing the 5-methyl, by N-methylation of the carbamate; by replacing the nitrogen with a carbon or removing the nitrogen to obtain a carboxylate; or by inserting an isomeric 5-methyl isoxazole. The effectiveness of these various chemical modifications in reducing GSH adduct formation is in line with the proposed mechanism. In conclusion, we have identified a novel mechanism of bioactivation of phenyl 5-methylisoxazol-4-yl-amines. The reactivity was attenuated by several modifications aimed to prevent the emergence of an enimine intermediate. Whether 5-methyl isoxazoles should be considered a structural alert for potential formation of reactive metabolites is dependent on their context, i.e., 4-nitrogen.

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

Cited by 11 publications

References 7 publications

GpTx‐1 and [Ala⁵, Phe⁶, Leu²⁶, Arg²⁸]GpTx‐1, two peptide Na_V1.7 inhibitors: analgesic and tolerance properties at the spinal level

GpTx‐1 and [Ala⁵, Phe⁶, Leu²⁶, Arg²⁸]GpTx‐1, two peptide Na_V1.7 inhibitors: analgesic and tolerance properties at the spinal level

Advances in Targeting Voltage‐Gated Sodium Channels with Small Molecules

Novel Bioactivation Mechanism of Reactive Metabolite Formation from Phenyl Methyl-Isoxazoles

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

Cited by 11 publications

References 7 publications

GpTx‐1 and [Ala5, Phe6, Leu26, Arg28]GpTx‐1, two peptide NaV1.7 inhibitors: analgesic and tolerance properties at the spinal level

GpTx‐1 and [Ala5, Phe6, Leu26, Arg28]GpTx‐1, two peptide NaV1.7 inhibitors: analgesic and tolerance properties at the spinal level

Advances in Targeting Voltage‐Gated Sodium Channels with Small Molecules

Novel Bioactivation Mechanism of Reactive Metabolite Formation from Phenyl Methyl-Isoxazoles

Contact Info

Product

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GpTx‐1 and [Ala⁵, Phe⁶, Leu²⁶, Arg²⁸]GpTx‐1, two peptide Na_V1.7 inhibitors: analgesic and tolerance properties at the spinal level

GpTx‐1 and [Ala⁵, Phe⁶, Leu²⁶, Arg²⁸]GpTx‐1, two peptide Na_V1.7 inhibitors: analgesic and tolerance properties at the spinal level