Discovery of non-zwitterionic aryl sulfonamides as Nav1.7 inhibitors with efficacy in preclinical behavioral models and translational measures of nociceptive neuron activation

Wu, Yong‐Jin; Guernon, Jason; McClure, Andrea; Luo, Guanglin; Rajamani, Ramkumar; Ng, Alicia; Easton, Amy; Newton, Amy; Bourin, Clotilde; Parker, Dawn D.; Mosure, Kathleen W.; Barnaby, Omar S.; Soars, Matthew G.; Knox, Ronald J.; Matchett, Michele; Pieschl, Rick L.; Herrington, James; Chen, Ping; Sivarao, Digavalli V.; Bristow, Linda J.; Meanwell, Nicholas A.; Bronson, Joanne J.; Olson, R. E.; Thompson, Lorin A.; Dzierba, Carolyn D.

doi:10.1016/j.bmc.2017.08.012

Cited by 19 publications

(13 citation statements)

References 25 publications

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“…However, this is amenable to improvement by replacing a more basic moiety with a less basic one. 70,71 We thus plotted the efflux ratios against the cap group's pK a , and the observed correlation is consistent with the foregoing postulate ( Figure S1). In light of the favorable cell line permeability data for SW-100, we next carried out brain/plasma PK studies in vivo.…”

Section: Sw-100 Displays a Significantly Improved Ability To Cross Thsupporting

confidence: 85%

Brain Penetrable Histone Deacetylase 6 Inhibitor SW-100 Ameliorates Memory and Learning Impairments in a Mouse Model of Fragile X Syndrome

Kozikowski

Shen

Pardo

et al. 2018

ACS Chem. Neurosci.

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S.J. oversaw the experimental design and data analyses of animal studies. University Health Network: D.S. designed and performed the dose-response tubulin acetylation studies in HEK293 cells and assisted in the preparation of the manuscript, and J.H.E. oversaw the experimental design and data analyses of the in vitro tubulin acetylation study. Leuven Research Institute for Neuroscience and Disease: V.B. designed and performed the tubulin/histone acetylation studies in N2a and assisted in the preparation of the manuscript; L.V.D.B. oversaw the experimental design and data analyses of the in vitro tubulin acetylation study. Promega Corporation: C.A.Z. designed and performed the cellular HDAC target engagement assay; M.B.R. oversaw the experimental design and data analyses of target engagement study and assisted in the preparation of the manuscript. Institute of Biotechnology of the Czech Academy of Sciences: Z.K. performed and confirmed the HDAC6 and HDAC11 data for SW-100. C.B. oversaw the experimental design and data analyses of HDAC enzyme studies.

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Section: Sw-100 Displays a Significantly Improved Ability To Cross Thsupporting

confidence: 85%

Brain Penetrable Histone Deacetylase 6 Inhibitor SW-100 Ameliorates Memory and Learning Impairments in a Mouse Model of Fragile X Syndrome

Kozikowski

Shen

Pardo

et al. 2018

ACS Chem. Neurosci.

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“…Though studies have shown utility of the new Nav1.7 aryl sulfonamide compounds for treating pain in various animal models (Focken et al, 2016;Flinspach et al, 2017;Pero et al, 2017;Wu et al, 2017;Sun et al, 2019), it is still unclear how effective they will be in humans, and for what conditions. Because of the unusual anionic nature of the compounds associated with the negatively charged "warhead", it is possible that tissue distribution may present unusual challenges and limit the concentration of compound that can be achieved at nerve endings or axons.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, a new class of small molecule inhibitors has been identified that interact with the sodium channel in a completely different manner (McCormack et al, 2013;Bagal et al, 2014;Focken et al, 2016Focken et al, , 2018Alexandrou et al, 2016;Flinspach et al, 2017;Pero et al, 2017;Wu et al, 2017Wu et al, , 2018. These molecules, based on an aryl sulfonamide scaffold, bind to the voltage sensor region of the fourth pseudosubunit domain (VSD4) at a site that is on the external side of the plasma membrane (McCormack et al, 2013;Ahuja et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Lidocaine Binding Enhances Inhibition of Nav1.7 Channels by the Sulfonamide PF-05089771

Bean

2020

Mol Pharmacol

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PF-05089771 is an aryl sulfonamide Nav1.7 channel blocker that binds to the inactivated state of Nav1.7 channels with high affinity but binds only weakly to channels in the resting state. Such aryl sulfonamide Nav1.7 channel blockers bind to the extracellular surface of the S1-S4 voltage sensor segment of homologous Domain 4, whose movement is associated with inactivation. This binding site is different from that of classical sodium channel inhibitors like lidocaine, which also bind with higher affinity to the inactivated state than the resting state, but bind at a site within the pore of the channel. The common dependence on gating state with distinct binding sites raises the possibility that inhibition by aryl sulfonamides and by classic local anesthetics might show an interaction mediated by their mutual state-dependence. We tested this possibility by examining the state-dependent inhibition by PF-05089771 and lidocaine of human Nav1.7 channels expressed in HEK293 cells. At-80 mV, where a small fraction of channels are in an inactivated state under drug-free conditions, inhibition by PF-05089771 was both enhanced and speeded in the presence of lidocaine. The results suggest that lidocaine binding to the channel enhances PF-05089771 inhibition by altering the equilibrium between resting states (with D4S4 in the inner position) and inactivated states (with D4S4 in the outer position). The gating state-mediated interaction between the compounds illustrates a principle applicable to many state-dependent agents. (228 words).

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“…Because of these clinical evidences, the hNa V 1.7 channel has been the target of choice for high-throughput screening campaigns to identify blockers as pain therapeutics. Two types of libraries were used for this purpose: small organic compounds from leading pharmaceutical companies (Macsari et al, 2012;Nguyen et al, 2012;Sun et al, 2014;Focken et al, 2016;Wu et al, 2017;Cuesta and Meneses, 2021) and natural peptides originating from animal venoms (Trim et al, 2021). Indeed, disulfide-bridged peptides, frequently purified from animal venoms, have been considered as interesting lead compounds (Bordon et al, 2020), either as pore blockers or gating modifiers, for the modulation of ion channels in general and the treatment of pain in particular (Cardoso and Lewis, 2018).…”

Section: Introductionmentioning

confidence: 99%

Synthetic Analogues of Huwentoxin-IV Spider Peptide With Altered Human NaV1.7/NaV1.6 Selectivity Ratios

Lopez

Montnach

Oliveira-Mendes

et al. 2021

Front. Cell Dev. Biol.

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Huwentoxin-IV (HwTx-IV), a peptide discovered in the venom of the Chinese bird spider Cyriopagopus schmidti, has been reported to be a potent antinociceptive compound due to its action on the genetically-validated NaV1.7 pain target. Using this peptide for antinociceptive applications in vivo suffers from one major drawback, namely its negative impact on the neuromuscular system. Although studied only recently, this effect appears to be due to an interaction between the peptide and the NaV1.6 channel subtype located at the presynaptic level. The aim of this work was to investigate how HwTx-IV could be modified in order to alter the original human (h) NaV1.7/NaV1.6 selectivity ratio of 23. Nineteen HwTx-IV analogues were chemically synthesized and tested for their blocking effects on the Na+ currents flowing through these two channel subtypes stably expressed in cell lines. Dose-response curves for these analogues were generated, thanks to the use of an automated patch-clamp system. Several key amino acid positions were targeted owing to the information provided by earlier structure-activity relationship (SAR) studies. Among the analogues tested, the potency of HwTx-IV E4K was significantly improved for hNaV1.6, leading to a decreased hNaV1.7/hNaV1.6 selectivity ratio (close to 1). Similar decreased selectivity ratios, but with increased potency for both subtypes, were observed for HwTx-IV analogues that combine a substitution at position 4 with a modification of amino acid 1 or 26 (HwTx-IV E1G/E4G and HwTx-IV E4K/R26Q). In contrast, increased selectivity ratios (>46) were obtained if the E4K mutation was combined to an additional double substitution (R26A/Y33W) or simply by further substituting the C-terminal amidation of the peptide by a carboxylated motif, linked to a marked loss of potency on hNaV1.6 in this latter case. These results demonstrate that it is possible to significantly modulate the selectivity ratio for these two channel subtypes in order to improve the potency of a given analogue for hNaV1.6 and/or hNaV1.7 subtypes. In addition, selective analogues for hNaV1.7, possessing better safety profiles, were produced to limit neuromuscular impairments.

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Discovery of non-zwitterionic aryl sulfonamides as Nav1.7 inhibitors with efficacy in preclinical behavioral models and translational measures of nociceptive neuron activation

Cited by 19 publications

References 25 publications

Brain Penetrable Histone Deacetylase 6 Inhibitor SW-100 Ameliorates Memory and Learning Impairments in a Mouse Model of Fragile X Syndrome

Brain Penetrable Histone Deacetylase 6 Inhibitor SW-100 Ameliorates Memory and Learning Impairments in a Mouse Model of Fragile X Syndrome

Lidocaine Binding Enhances Inhibition of Nav1.7 Channels by the Sulfonamide PF-05089771

Synthetic Analogues of Huwentoxin-IV Spider Peptide With Altered Human NaV1.7/NaV1.6 Selectivity Ratios

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