The discovery of a potent Na<sub>v</sub>1.3 inhibitor with good oral pharmacokinetics

Pryde, David C.; Swain, Nigel A.; Stupple, Paul A.; West, Christopher W.; Marron, Brian E.; Markworth, Christopher J.; Printzenhoff, David; Lin, Zhiwu; Cox, Peter; Suzuki, Ritsuro; McMurray, Sheridan; Waldron, Grace; Payne, C. Elizabeth; Warmus, Joseph S.; Chapman, Mark L.

doi:10.1039/c7md00131b

Cited by 6 publications

(8 citation statements)

References 30 publications

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“…This difference may be related to the predominant expression of the Na v 1.3 isoform in human lymph vessels (Telinius et al, 2015), since ranolazine selectively blocks several sodium channel isoforms (Na v 1.4, 1.5, 1.7, and 1.8) but fails to block Na v 1.3 whereas TTX is a nonselective sodium channel antagonist that inhibits all isoforms. Accordingly, the clinical use of ranolazine and other sodium channel blockers have not been associated with lymphedema (Dokken and Fairley, 2021), although recent efforts to develop Na v 1.3 selective blockers raise the possibility that these medications may have unintended effects on the lymphatic circulation (Keppel Hesselink, 2017;Pryde et al, 2017;Su et al, 2017).…”

Section: Sodium Channel Blockers (Class I)mentioning

confidence: 99%

Drug-Related Lymphedema: Mysteries, Mechanisms, and Potential Therapies

Pal

Rahman

et al. 2022

Front. Pharmacol.

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The lymphatic circulation is an important component of the circulatory system in humans, playing a critical role in the transport of lymph fluid containing proteins, white blood cells, and lipids from the interstitial space to the central venous circulation. The efficient transport of lymph fluid critically relies on the rhythmic contractions of collecting lymph vessels, which function to “pump” fluid in the distal to proximal direction through the lymphatic circulation with backflow prevented by the presence of valves. When rhythmic contractions are disrupted or valves are incompetent, the loss of lymph flow results in fluid accumulation in the interstitial space and the development of lymphedema. There is growing recognition that many pharmacological agents modify the activity of ion channels and other protein structures in lymph muscle cells to disrupt the cyclic contraction and relaxation of lymph vessels, thereby compromising lymph flow and predisposing to the development of lymphedema. The effects of different medications on lymph flow can be understood by appreciating the intricate intracellular calcium signaling that underlies the contraction and relaxation cycle of collecting lymph vessels. For example, voltage-sensitive calcium influx through long-lasting (“L-type”) calcium channels mediates the rise in cytosolic calcium concentration that triggers lymph vessel contraction. Accordingly, calcium channel antagonists that are mainstay cardiovascular medications, attenuate the cyclic influx of calcium through L-type calcium channels in lymph muscle cells, thereby disrupting rhythmic contractions and compromising lymph flow. Many other classes of medications also may contribute to the formation of lymphedema by impairing lymph flow as an off-target effect. The purpose of this review is to evaluate the evidence regarding potential mechanisms of drug-related lymphedema with an emphasis on common medications administered to treat cardiovascular diseases, metabolic disorders, and cancer. Additionally, although current pharmacological approaches used to alleviate lymphedema are largely ineffective, efforts are mounting to arrive at a deeper understanding of mechanisms that regulate lymph flow as a strategy to identify novel anti-lymphedema medications. Accordingly, this review also will provide information on studies that have explored possible anti-lymphedema therapeutics.

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Section: Sodium Channel Blockers (Class I)mentioning

confidence: 99%

Drug-Related Lymphedema: Mysteries, Mechanisms, and Potential Therapies

Pal

Rahman

et al. 2022

Front. Pharmacol.

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“…These observations fit well with our cellular data because DRG neurons were ‘axotomized’ during the isolation procedure and may then upregulate Na V 1.3 in culture. Neuropathic pain resulting from nerve damage has been linked to Na V 1.3 overexpression, but currently this target is not addressed by specific analgesics [54,55]. Research tools such as MeuNaTxα‐1, BeM9, and msBeM9 may be valuable in this context.…”

Section: Discussionmentioning

confidence: 99%

Scorpion toxin MeuNaTxα‐1 sensitizes primary nociceptors by selective modulation of voltage‐gated sodium channels

et al. 2020

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Nociceptors are specialized sensory neurons that initiate the perception of pain. We applied high content screening microscopy to screen animal venoms for toxins, which activate pain enhancing signal transduction in sensory neurons. We identified the scorpion α‐toxin MeuNaTxα‐1 from Mesobuthus eupeus, which selectively affected tetrodotoxin‐sensitive voltage‐gated sodium channels, in particular NaV1.2, and thereby depolarized the nociceptors, leading to calcium influx, subsequent PKA‐II activation, and thermal hyperalgesia.

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“…Diphenylmethyl amide adducts of an aryl sulphonamide series (44) Channel block Not yet tested in the clinic Na v 1.7 Lacosemide Inactivated state blocker Safe and effective, in a randomized, placebo-controlled, double-blind, crossover-design study of Na v 1.7 related small fiber neuropathy (45) PF-05089771 Inactivated state blocker Failed to reach therapeutic end point in a diabetic neuropathy trial (46) CNV1014802 (vixotrigine or raxatrigine) Inactivated state blocker Trial ongoing for effectiveness in trigeminal neuralgia (47).…”

Section: Not Yet Tested In the Clinicmentioning

confidence: 99%

“…Tap1a also blocks Cav3.2 channels (49). compounds with good selectivity for Na v 1.3 as well as favorable pharmacokinetics (44).…”

Section: Not Yet Tested In the Clinicmentioning

confidence: 99%

“…Because Na v 1.3 is mainly present in embryonic and early neonatal animals and because nerve injury promotes selective upregulation of Na v 1.3 in nociceptive pathways of adults, there is considerable interest in developing Na v 1.3 blockers. Structure activity studies starting with a diphenylmethyl amide adduct of an aryl sulphonamide has led to the development of compounds with good selectivity for Na v 1.3 as well as favorable pharmacokinetics ( 44 ).…”

Section: Voltage-gated Na + Channelsmentioning

confidence: 99%

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Peripheral Voltage-Gated Cation Channels in Neuropathic Pain and Their Potential as Therapeutic Targets

Alles

Smith

2021

Front. Pain Res.

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The persistence of increased excitability and spontaneous activity in injured peripheral neurons is imperative for the development and persistence of many forms of neuropathic pain. This aberrant activity involves increased activity and/or expression of voltage-gated Na+ and Ca2+ channels and hyperpolarization activated cyclic nucleotide gated (HCN) channels as well as decreased function of K+ channels. Because they display limited central side effects, peripherally restricted Na+ and Ca2+ channel blockers and K+ channel activators offer potential therapeutic approaches to pain management. This review outlines the current status and future therapeutic promise of peripherally acting channel modulators. Selective blockers of Nav1.3, Nav1.7, Nav1.8, Cav3.2, and HCN2 and activators of Kv7.2 abrogate signs of neuropathic pain in animal models. Unfortunately, their performance in the clinic has been disappointing; some substances fail to meet therapeutic end points whereas others produce dose-limiting side effects. Despite this, peripheral voltage-gated cation channels retain their promise as therapeutic targets. The way forward may include (i) further structural refinement of K+ channel activators such as retigabine and ASP0819 to improve selectivity and limit toxicity; use or modification of Na+ channel blockers such as vixotrigine, PF-05089771, A803467, PF-01247324, VX-150 or arachnid toxins such as Tap1a; the use of Ca2+ channel blockers such as TTA-P2, TTA-A2, Z 944, ACT709478, and CNCB-2; (ii) improving methods for assessing “pain” as opposed to nociception in rodent models; (iii) recognizing sex differences in pain etiology; (iv) tailoring of therapeutic approaches to meet the symptoms and etiology of pain in individual patients via quantitative sensory testing and other personalized medicine approaches; (v) targeting genetic and biochemical mechanisms controlling channel expression using anti-NGF antibodies such as tanezumab or re-purposed drugs such as vorinostat, a histone methyltransferase inhibitor used in the management of T-cell lymphoma, or cercosporamide a MNK 1/2 inhibitor used in treatment of rheumatoid arthritis; (vi) combination therapy using drugs that are selective for different channel types or regulatory processes; (vii) directing preclinical validation work toward the use of human or human-derived tissue samples; and (viii) application of molecular biological approaches such as clustered regularly interspaced short palindromic repeats (CRISPR) technology.

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The discovery of a potent Na_v1.3 inhibitor with good oral pharmacokinetics

Cited by 6 publications

References 30 publications

Drug-Related Lymphedema: Mysteries, Mechanisms, and Potential Therapies

Drug-Related Lymphedema: Mysteries, Mechanisms, and Potential Therapies

Scorpion toxin MeuNaTxα‐1 sensitizes primary nociceptors by selective modulation of voltage‐gated sodium channels

Peripheral Voltage-Gated Cation Channels in Neuropathic Pain and Their Potential as Therapeutic Targets

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The discovery of a potent Nav1.3 inhibitor with good oral pharmacokinetics

Cited by 6 publications

References 30 publications

Drug-Related Lymphedema: Mysteries, Mechanisms, and Potential Therapies

Drug-Related Lymphedema: Mysteries, Mechanisms, and Potential Therapies

Scorpion toxin MeuNaTxα‐1 sensitizes primary nociceptors by selective modulation of voltage‐gated sodium channels

Peripheral Voltage-Gated Cation Channels in Neuropathic Pain and Their Potential as Therapeutic Targets

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The discovery of a potent Na_v1.3 inhibitor with good oral pharmacokinetics