Dataset Information

Discovery of Aryl Sulfonamides as Isoform-Selective Inhibitors of NaV1.7 with Efficacy in Rodent Pain Models.

ABSTRACT: We report on a novel series of aryl sulfonamides that act as nanomolar potent, isoform-selective inhibitors of the human sodium channel hNaV1.7. The optimization of these inhibitors is described. We aimed to improve potency against hNaV1.7 while minimizing off-target safety concerns and generated compound 3. This agent displayed significant analgesic effects in rodent models of acute and inflammatory pain and demonstrated that binding to the voltage sensor domain 4 site of NaV1.7 leads to an analgesic effect in vivo. Our findings corroborate the importance of hNaV1.7 as a drug target for the treatment of pain.

SUBMITTER: Focken T

PROVIDER: S-EPMC4789675 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Publications

Discovery of Aryl Sulfonamides as Isoform-Selective Inhibitors of NaV1.7 with Efficacy in Rodent Pain Models.

Focken Thilo T Liu Shifeng S Chahal Navjot N Dauphinais Maxim M Grimwood Michael E ME Chowdhury Sultan S Hemeon Ivan I Bichler Paul P Bogucki David D Waldbrook Matthew M Bankar Girish G Sojo Luis E LE Young Clint C Lin Sophia S Shuart Noah N Kwan Rainbow R Pang Jodie J Chang Jae H JH Safina Brian S BS Sutherlin Daniel P DP Johnson J P JP Dehnhardt Christoph M CM Mansour Tarek S TS Oballa Renata M RM Cohen Charles J CJ Robinette C Lee CL

ACS medicinal chemistry letters 20160119 3

We report on a novel series of aryl sulfonamides that act as nanomolar potent, isoform-selective inhibitors of the human sodium channel hNaV1.7. The optimization of these inhibitors is described. We aimed to improve potency against hNaV1.7 while minimizing off-target safety concerns and generated compound 3. This agent displayed significant analgesic effects in rodent models of acute and inflammatory pain and demonstrated that binding to the voltage sensor domain 4 site of NaV1.7 leads to an ana ...[more]

PMID: 26985315

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Project description:Strong human genetic evidence points to an essential contribution of the voltage-gated sodium channel Nav1.7 to pain sensation: loss of Nav1.7 function leads to congenital insensitivity to pain, whereas gain-of-function mutations in the SCN9A gene that encodes Nav1.7 cause painful neuropathies, such as inherited erythromelalgia, a syndrome characterized by episodic spontaneous pain. Selective Nav1.7 channel blockers thus hold promise as potential painkillers with improved safety and reduced unwanted side effects compared with existing therapeutics. To determine the maximum effect of a theoretically perfectly selective Nav1.7 inhibitor, we generated a tamoxifen-inducible KO mouse model enabling genetic deletion of Nav1.7 from adult mice. Electrophysiological recordings of sensory neurons from these mice following tamoxifen injection demonstrated the loss of Nav1.7 channel current and the resulting decrease in neuronal excitability of small-diameter neurons. We found that behavioral responses to most, but surprisingly not all, modalities of noxious stimulus are abolished following adult deletion of Nav1.7, pointing toward indications where Nav1.7 blockade should be efficacious. Furthermore, we demonstrate that isoform-selective acylsulfonamide Nav1.7 inhibitors show robust analgesic and antinociceptive activity acutely after a single dose in mouse pain models shown to be Nav1.7-dependent. All experiments were done with both male and female mice. Collectively, these data expand the depth of knowledge surrounding Nav1.7 biology as it relates to pain, and provide preclinical proof of efficacy that lays a clear path toward translation for the therapeutic use of Nav1.7-selective inhibitors in humans.SIGNIFICANCE STATEMENT Loss-of-function mutations in the sodium channel Nav1.7 cause congenital insensitivity to pain in humans, making Nav1.7 a top target for novel pain drugs. Targeting Nav1.7 selectively has been challenging, however, in part due to uncertainties in which rodent pain models are dependent on Nav1.7. We have developed and characterized an adult-onset Nav1.7 KO mouse model that allows us to determine the expected effects of a theoretically perfect Nav1.7 blocker. Importantly, many commonly used pain models, such as mechanical allodynia after nerve injury, appear to not be dependent on Nav1.7 in the adult. By defining which models are Nav1.7 dependent, we demonstrate that selective Nav1.7 inhibitors can approximate the effects of genetic loss of function, which previously has not been directly established.

Dataset Information

Discovery of Aryl Sulfonamides as Isoform-Selective Inhibitors of NaV1.7 with Efficacy in Rodent Pain Models.

Publications

Discovery of Aryl Sulfonamides as Isoform-Selective Inhibitors of NaV1.7 with Efficacy in Rodent Pain Models.

Similar Datasets

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