Discovery of selective, orally bioavailable, N -linked arylsulfonamide Na v 1.7 inhibitors with pain efficacy in mice

Roecker, Anthony J.; Egbertson, Melissa S.; Jones, Kristen L.; Gomez, Robert; Kraus, Richard L.; Li, Yuxing; Koser, Amy Jo; Urban, Mark O.; Klein, Rebecca; Clements, Michelle K.; Panigel, Jacqueline; Daley, Christopher; Wang, Jixin; Finger, Eleftheria N.; Majercak, John; Santarelli, Vincent P.; Gregan, Irene; Cato, Matthew J.; Filzen, Tracey; Jovanovska, Aneta; Wang, Yinghong; Wang, Deping; Joyce, Leo A.; Sherer, Edward C.; Peng, Xuanjia; Wang, Xiu; Sun, Haiyan; Coleman, Paul J.; Houghton, Andrea K.; Layton, M. E.

doi:10.1016/j.bmcl.2017.03.085

Cited by 37 publications

(24 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The values for the IC 50 that we report are lower than those reported previously for PF-771 (3.9 nM versus 11 nM) or MRL5 (3.1 nM versus 8 nM; Alexandrou et al, 2016;Roecker et al, 2017), and this results in a higher multiple of IC 50 needed for efficacy. Our lower values are not inconsistent with earlier reports; rather, they arise because we measure block after holding for 25 min at a voltage that inactivates all channels and correct for possible run down or slow inactivation.…”

Section: Discussioncontrasting

confidence: 87%

“…The solid curve is a 1:1 binding isotherm with an EC 50 = 97 mM. This figure also shows the efficacy in the IEM assay for MRL5, which is compound 5 in a recent report from Merck Research Laboratories (Roecker et al, 2017), and for PF-771. MRL5 was evaluated because it is much less protein bound than the other arylsulfonamides that we have presented and is approximately equipotent with GX-044 for block of hNa V 1.7 (the authors report a free fraction of 0.41 and we find 0.22).…”

Section: Analgesic Activity Of Arylsulfonamides and Referencementioning

confidence: 75%

See 1 more Smart Citation

Selective NaV1.7 Antagonists with Long Residence Time Show Improved Efficacy against Inflammatory and Neuropathic Pain

et al. 2018

View full text Add to dashboard Cite

Selective block of Na1.7 promises to produce non-narcotic analgesic activity without motor or cognitive impairment. Several Na1.7-selective blockers have been reported, but efficacy in animal pain models required high multiples of the IC for channel block. Here, we report a target engagement assay using transgenic mice that has enabled the development of a second generation of selective Nav1.7 inhibitors that show robust analgesic activity in inflammatory and neuropathic pain models at low multiples of the IC. Like earlier arylsulfonamides, these newer acylsulfonamides target a binding site on the surface of voltage sensor domain 4 to achieve high selectivity among sodium channel isoforms and steeply state-dependent block. The improved efficacy correlates with very slow dissociation from the target channel. Chronic dosing increases compound potency about 10-fold, possibly due to reversal of sensitization arising during chronic injury, and provides efficacy that persists long after the compound has cleared from plasma.

show abstract

Section: Discussioncontrasting

confidence: 87%

Section: Analgesic Activity Of Arylsulfonamides and Referencementioning

confidence: 75%

Selective NaV1.7 Antagonists with Long Residence Time Show Improved Efficacy against Inflammatory and Neuropathic Pain

et al. 2018

View full text Add to dashboard Cite

show abstract

“…In animal models compounds inhibiting Na V 1.7 have demonstrated reductions in itch and pain. 173,174 Holistic treatments Given the psychological toll of chronic itch, it is not surprising that methods of stress or anxiety reduction can also reduce itch. 175 The effects of cognitive-behavioral therapy on reducing itch have been reported in patients with AD.…”

Section: Treatments On the Horizonmentioning

confidence: 99%

Itch: From mechanism to (novel) therapeutic approaches

Yosipovitch

Rosen

Hashimoto

2018

Journal of Allergy and Clinical Immunology

249

307

View full text Add to dashboard Cite

Itch is a common sensory experience that is prevalent in patients with inflammatory skin diseases, as well as in those with systemic and neuropathic conditions. In patients with these conditions, itch is often severe and significantly affects quality of life. Itch is encoded by 2 major neuronal pathways: histaminergic (in acute itch) and nonhistaminergic (in chronic itch). In the majority of cases, crosstalk existing between keratinocytes, the immune system, and nonhistaminergic sensory nerves is responsible for the pathophysiology of chronic itch. This review provides an overview of the current understanding of the molecular, neural, and immune mechanisms of itch: beginning in the skin, proceeding to the spinal cord, and eventually ascending to the brain, where itch is processed. A growing understanding of the mechanisms of chronic itch is expanding, as is our pipeline of more targeted topical and systemic therapies. Our therapeutic armamentarium for treating chronic itch has expanded in the last 5 years, with developments of topical and systemic treatments targeting the neural and immune systems.

show abstract

“…Na v channels are involved in a wide array of physiological processes. In particular, Na v 1.7 was clearly identified as playing a crucial role in nociceptive pathways, which led to research into the development of novel therapeutics for pain treatment [6,7,8,9,10,11,12,13,14,15,16,17,18]. For examples, missense mutations of the SCN9A gene that encodes Na v 1.7 produces congenital indifference to pain [19].…”

Section: Introductionmentioning

confidence: 99%

Chemical Synthesis, Proper Folding, Nav Channel Selectivity Profile and Analgesic Properties of the Spider Peptide Phlotoxin 1

Nicolas

Zoukimian

Bosmans

et al. 2019

Toxins

View full text Add to dashboard Cite

Phlotoxin-1 (PhlTx1) is a peptide previously identified in tarantula venom (Phlogius species) that belongs to the inhibitory cysteine-knot (ICK) toxin family. Like many ICK-based spider toxins, the synthesis of PhlTx1 appears particularly challenging, mostly for obtaining appropriate folding and concomitant suitable disulfide bridge formation. Herein, we describe a procedure for the chemical synthesis and the directed sequential disulfide bridge formation of PhlTx1 that allows for a straightforward production of this challenging peptide. We also performed extensive functional testing of PhlTx1 on 31 ion channel types and identified the voltage-gated sodium (Nav) channel Nav1.7 as the main target of this toxin. Moreover, we compared PhlTx1 activity to 10 other spider toxin activities on an automated patch-clamp system with Chinese Hamster Ovary (CHO) cells expressing human Nav1.7. Performing these analyses in reproducible conditions allowed for classification according to the potency of the best natural Nav1.7 peptide blockers. Finally, subsequent in vivo testing revealed that intrathecal injection of PhlTx1 reduces the response of mice to formalin in both the acute pain and inflammation phase without signs of neurotoxicity. PhlTx1 is thus an interesting toxin to investigate Nav1.7 involvement in cellular excitability and pain.

show abstract

Discovery of selective, orally bioavailable, N -linked arylsulfonamide Na v 1.7 inhibitors with pain efficacy in mice

Cited by 37 publications

References 41 publications

Selective NaV1.7 Antagonists with Long Residence Time Show Improved Efficacy against Inflammatory and Neuropathic Pain

Selective NaV1.7 Antagonists with Long Residence Time Show Improved Efficacy against Inflammatory and Neuropathic Pain

Itch: From mechanism to (novel) therapeutic approaches

Chemical Synthesis, Proper Folding, Nav Channel Selectivity Profile and Analgesic Properties of the Spider Peptide Phlotoxin 1

Contact Info

Product

Resources

About