Benzoxazolinone aryl sulfonamides as potent, selective Na v 1.7 inhibitors with in vivo efficacy in a preclinical pain model

Pero, Joseph E.; Rossi, Michael; Lehman, Hannah D.G.F.; Kelly, Michael J.; Mulhearn, James; Wolkenberg, S. E.; Cato, Matthew J.; Clements, Michelle K.; Daley, Christopher; Filzen, Tracey; Finger, Eleftheria N.; Gregan, Yun; Henze, Darrell A.; Jovanovska, Aneta; Klein, Rebecca; Kraus, Richard L.; Li, Yuxing; Liang, Annie; Majercak, John; Panigel, Jacqueline; Urban, Mark O.; Wang, Jixin; Wang, Yinghong; Houghton, Andrea K.; Layton, M. E.

doi:10.1016/j.bmcl.2017.04.040

Cited by 35 publications

(26 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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%

See 1 more Smart Citation

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

Bean

2020

Mol Pharmacol

View full text Add to dashboard Cite

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).

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Bean

2020

Mol Pharmacol

View full text Add to dashboard Cite

show abstract

“…(8) Examples include a cystine knot toxin that binds to VSD II and select sulfonamide inhibitors that bind to VSD IV. (44,(51)(52)(53). For this latter class of inhibitors, determining the level 40 of NaV1.7 target occupancy reached at these exposures is difficult given the variation in potency (i.e., IC50 values determined by electrophysiology) against resting and inactivated conformational states of the channel.…”

Section: Discussionmentioning

confidence: 99%

Discovery of a Selective, State-Independent Inhibitor of Na_V1.7 by Modification of Guanidinium Toxins

Pajouhesh

Beckley

Delwig

et al. 2019

Preprint

View full text Add to dashboard Cite

The voltage-gated sodium channel isoform NaV1.7 is highly expressed in small diameter dorsal root ganglion neurons and is obligatory for nociceptive signal transmission. Genetic gainof-function and loss-of-function NaV1.7 mutations have been identified in select individuals, and are associated with episodic extreme pain disorders and insensitivity to pain, respectively. These 20 35 addiction. Voltage-gated sodium ion channels (NaVs) have emerged as promising targets for the development of non-opioid pain medicines. NaVs are involved in the propagation of electrical signals along neurons throughout the body. Humans born without a functional copy of one sodium channel subtype, NaV1.7, are unable to experience most types of pain. In the present work, we disclose the discovery and characterization of a selective inhibitor of NaV1.7 that reduces 40 sensitivity to a painful thermal stimulus in non-human primates. Findings from this work may help guide the development of novel, non-addictive drug candidates as alternatives to opioids.

show abstract

“…All animal studies were conducted in accord with the Guide for the Care and Use of Laboratory Animals (Institute of Laboratory Animal Resources, Commission on Life Sciences, National Research Council, 2011) and were approved by the Institutional Animal Care and Use Committee at MRL, Merck & Co. Rat Dorsal Root Ganglion were harvested as descriped 29 .…”

Section: Methodsmentioning

confidence: 99%

Comparison of the Rat and Human Dorsal Root Ganglion Proteome

Schwaid

Krasowka-Zoladek

Chen

et al. 2018

Sci Rep

View full text Add to dashboard Cite

Dorsal root ganglion (DRG) are a key tissue in the nervous system that have a role in neurological disease, particularly pain. Despite the importance of this tissue, the proteome of DRG is poorly understood, and it is unknown whether the proteome varies between organisms or different DRG along the spine. Therefore, we profiled the proteome of human and rat DRG. We identified 5,245 proteins in human DRG and 4959 proteins in rat DRG. Across species the proteome is largely conserved with some notable differences. While the most abundant proteins in both rat and human DRG played a role in extracellular functions and myelin sheeth, proteins detected only in humans mapped to roles in immune function whereas those detected only in rat mapped to roles in localization and transport. The DRG proteome between human T11 and L2 vertebrae was nearly identical indicating DRG from different vertebrae are representative of one another. Finally, we asked if this data could be used to enhance translatability by identifying mechanisms that modulate cellular phenotypes representative of pain in different species. Based on our data we tested and discovered that MAP4K4 inhibitor treatment increased neurite outgrowth in rat DRG as in human SH-SY5Y cells.

show abstract

Benzoxazolinone aryl sulfonamides as potent, selective Na v 1.7 inhibitors with in vivo efficacy in a preclinical pain model

Cited by 35 publications

References 31 publications

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

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

Discovery of a Selective, State-Independent Inhibitor of Na_V1.7 by Modification of Guanidinium Toxins

Comparison of the Rat and Human Dorsal Root Ganglion Proteome

Contact Info

Product

Resources

About

Benzoxazolinone aryl sulfonamides as potent, selective Na v 1.7 inhibitors with in vivo efficacy in a preclinical pain model

Cited by 35 publications

References 31 publications

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

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

Discovery of a Selective, State-Independent Inhibitor of NaV1.7 by Modification of Guanidinium Toxins

Comparison of the Rat and Human Dorsal Root Ganglion Proteome

Contact Info

Product

Resources

About

Discovery of a Selective, State-Independent Inhibitor of Na_V1.7 by Modification of Guanidinium Toxins