PF-05089771 / Pfizer - LARVOL DELTA

BOTH TETRODOTOXIN-SENSITIVE AND TETRODOTOXIN-RESISTANT VOLTAGE-GATED SODIUM CHANNELS (NAV1S) CONTRIBUTE TO VAGAL MECHANOSENSITIVE AFFERENT ACTIVATION BY ESOPHAGEAL DISTENTION. (DDW 2025) - "Using selective pharmacological inhibitors (PF05089771, ICA121341 and LSN3049227), we found that inhibition of individual TTX-sensitive Na V 1s had little effect on AP initiation from afferent terminals. In conclusion, these data indicate that vagal activation by esophageal stretch is mediated by multiple Na V 1 isoforms. Furthermore, although Na V 1.8 cannot initiate APs alone (i.e. during TTX treatment), we find evidence of cooperativity between Na V 1.8 and TTX-sensitive Na V 1s for initiating APs in response to mechanical distention."

CNS Disorders • Epilepsy • Gastrointestinal Disorder • Pain • NAV1

Effectiveness of selective NaV1.7 blocker PF-05089771 in reducing cough associated with allergic rhinitis in guinea pigs. (PubMed, Respir Physiol Neurobiol) - "NaV1.7 blocker inhalation effectively inhibits cough in guinea pigs with AR."

Journal • Allergic Rhinitis • Chronic Cough • Cough • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • NAV1

Unexpected contribution of NaV1.8 to TTX-sensitive action potential conduction in human and rodent vagus nerves (Neuroscience 2024) - "Our studies in mice and rats show that tetrodotoxin (TTX, 300nM) completely abolished vagal A- and C-wave CAPs indicating that TTX-sensitive NaV1s are essential for all AP conduction. PF-05089771 (mouse NaV1.7 blocker) and ProTX-II (rat NaV1.7 blocker) significantly reduced both the A- (50% reduction) and C-waves (75% reduction) of mouse and rat CAP respectively, suggesting a predominant role for the TTX-sensitive NaV1.7...Our results show that TTX-sensitive channels (mainly Nav1.7) and TTX-resistant NaV1.8 cooperate in vagal AP conduction such that both are required for most vagal fibers. Pharmacological inhibition of NaV1.8 in the vagus nerve may have profound effects on autonomic regulation of visceral organs."

Preclinical • CNS Disorders • NAV1

The selective blocker of voltage-gated sodium channels NaV1.7 PF-05089771 has the potential to inhibit cough in guinea pigs with allergic rhinitis (ERS 2024) - "NaV1.7 blocker inhalation inhibited the stimulating effect of experimental allergic rhinitis on cough in awake guinea pigs. Supported by VEGA No. 1/0030/24 and APVV-22-0052."

Allergic Rhinitis • Chronic Cough • Cough • Immunology • Inflammation • Respiratory Diseases • NAV1

Role of NaV1.7 in postganglionic sympathetic nerve function in human and guinea-pig arteries. (PubMed, J Physiol) - "Electrical field stimulation (EFS) induced rapid contractions in guinea-pig isolated aorta, pulmonary arteries, and human isolated pulmonary arteries via stimulation of intrinsic nerves, which were inhibited by prazosin or the NaV1 blocker tetrodotoxin...NaV1.7 blockade substantially inhibits sympathetic nerve-mediated adrenergic contractions in human and guinea-pig blood vessels. Pharmacologically blocking NaV1.7 profoundly affects sympathetic and parasympathetic responses in addition to sensory fibres, prompting exploration into the broader physiological consequences of NaV1.7 mutations on autonomic nerve activity."

Journal • Pain • NAV1

Similar excitability through different sodium channels and implications for the analgesic efficacy of selective drugs. (PubMed, Elife) - "A similar shift in NaV dependence occurs in vivo after inflammation, impacting ability of the NaV1.7-selective inhibitor PF-05089771 to reduce pain in behavioral tests...Identifying the dominant NaV subtype to predict drug efficacy is not trivial. Degeneracy at the cellular level must be considered when choosing drug targets at the molecular level."

Journal • Inflammation • Pain • NAV1

Mechanism of Human Cold Pain Perception - Involvement of TRPA1, TRPM8, Nav1.7 and Nav1.8 (clinicaltrials.gov) - P1 | N=36 | Completed | Sponsor: Medical University of Vienna | Not yet recruiting ➔ Completed

Trial completion • Pain

Action potential conduction in the mouse and rat vagus nerve is dependent on multiple voltage-gated sodium channels (Na1s). (PubMed, J Neurophysiol) - "We studied the A- and C-waves of electrically-stimulated compound action potentials (CAP) of the mouse and rat vagus nerves with and without Na1 inhibitor administration: tetrodotoxin (TTX), PF-05089771 (mouse Na1.7), ProTX-II (Na1.7), ICA-121341 (Na1.1, Na1.3, Na1.6), LSN-3049227 (Na1.2, Na1.6, Na1.7) and A-803467 (Na1.8). Overall, our data demonstrate that multiple Na1 subtypes contribute to vagal CAPs, with Na1.7 and Na1.8 playing predominant roles and Na1.6 and Na1.2 contributing to a different extent based upon nerve fiber type and species. Inhibition of these Na1 may impact autonomic regulation of visceral organs."

Journal • Preclinical

Mechanism of Human Cold Pain Perception - Involvement of TRPA1, TRPM8, Nav1.7 and Nav1.8 (clinicaltrials.gov) - P1 | N=36 | Not yet recruiting | Sponsor: Medical University of Vienna

New P1 trial • Pain

Nav1.7 is essential for nociceptor action potentials in the mouse in a manner independent of endogenous opioids. (PubMed, Neuron) - "Using behavioral pharmacology and single-cell RNA-seq analysis, we find that overexpression of enkephalin occurs only in cLTMR neurons, a subclass of sensory neurons involved in low-threshold touch detection, and that this overexpression does not play a role in the analgesia observed following genetic removal of Nav1.7. Furthermore, we demonstrate using laser speckle contrast imaging (LSCI) and in vivo electrophysiology that Nav1.7 function is required for the initiation of C-fiber action potentials (APs), which explains the observed insensitivity to pain following genetic removal or inhibition of Nav1.7."

Journal • Preclinical • Addiction (Opioid and Alcohol) • Pain

Ectopic expression of Nav1.7 in spinal dorsal horn neurons induced by NGF contributes to neuropathic pain in a mouse spinal cord injury model. (PubMed, Front Mol Neurosci) - "Pharmacologic studies demonstrated that the efficacy of the blood-brain-barrier (BBB) permeable Nav1.7 inhibitor GNE-0439 for attenuation of NP in SCI mice was significantly better than that of the BBB non-permeable Nav1.7 inhibitor PF-05089771...In conclusion, our findings showed that the upregulation of Nav1.7 was induced by SCI in both SDH and DRG neurons through increased expression of NGF/JUN, and the inhibition of Nav1.7 in both peripheral and spinal neurons alleviated mechanical pain in SCI mice. These data suggest that BBB permeable Nav1.7 blockers might relieve NP in patients with SCI and that blocking the upregulation of Nav1.7 in the early stage of SCI via selective inhibition of the downstream signaling pathways of NGF or Nav1.7-targeted RNA drugs could be a strategy for therapy of SCI-induced NP."

Journal • Preclinical • CNS Disorders • Neuralgia • Orthopedics • Pain • NGF

Influence of combined voltage-gated sodium channel Na1.7 and Na1.8 inhibitors on cough in a guinea pig model. (PubMed, Respir Physiol Neurobiol) - "In this study, we demonstrated that inhaled aerosol of Na1.7 inhibitor PF-05089771 (10μM) and Na1.8 inhibitor A-803467 (1mM) mixture inhibited the capsaicin-induced cough by ≈60% and citric acid-induced cough by ≈65% at doses that did not modify respiratory rate. Our previous and present studies indicate that Na1.7 and Na1.8 may present promising therapeutic targets for antitussive therapy."

Journal • Preclinical • Cough • Respiratory Diseases

Action potential conduction in the mouse and rat vagus nerve is dependent on multiple tetrodotoxin sensitive voltage-gated sodium channels (NaV1s) (Neuroscience 2022) - "We measured the amplitude of the A- and C-waves in the CAP under control conditions and following the administration of selective NaV1 inhibitors such as TTX, PF-05089771 (PF), ICA-121341 (ICA), LSN-3049227 (LSN) and ProTX-II. Overall, our data indicates that multiple NaV1 subtypes (TTX-sensitive) contribute to vagal CAPs. Our findings also indicate that there is inter-species variability in the contribution of each subtype to vagal CAP conduction."

Preclinical • CNS Disorders • Pain

Long-Term Blockade of Nociceptive Na1.7 Channels Is Analgesic in Rat Models of Knee Arthritis. (PubMed, Biomolecules) - "This study examined the effect of Na1.7 blockade on joint pain using either the small molecule inhibitor PF05089771 or an antibody directed towards the intracellular domain of the ion channel...These data indicate that joint pain associated with neural demyelination can be alleviated somewhat by Na1.7 channel blockade. Biologics that inactivate Na1.7 channels have the potential to reduce arthritis pain over a protracted period of time."

Journal • Preclinical • Immunology • Musculoskeletal Diseases • Musculoskeletal Pain • Neuralgia • Orthopedics • Osteoarthritis • Pain • Rheumatology

Functional expression of Na1.7 channels in freshly dispersed mouse bronchial smooth muscle cells. (PubMed, Am J Physiol Cell Physiol) - "The current was highly sensitive to tetrodotoxin (IC=1.5 nM) and the Na1.7 subtype selective blocker, PF-05089771 (IC=8.6 nM), consistent with Na1.7 as the underlying pore-forming a subunit. These effects were readily reversed to control-like activity by tetrodotoxin (100 nM). In conclusion, mouse bronchial SMC functionally express Na1.7 channels that are capable of modulating contractile activity, at least under experimental conditions."

Journal • Preclinical

Peripheral Voltage-Gated Cation Channels in Neuropathic Pain and Their Potential as Therapeutic Targets. (PubMed, Front Pain Res (Lausanne)) - "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 Ca 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..."

Journal • Review • Hematological Malignancies • Immunology • Inflammatory Arthritis • Lymphoma • Neuralgia • Oncology • Pain • Rheumatoid Arthritis • Rheumatology • T Cell Non-Hodgkin Lymphoma • TAP1

Histamine Sensitization of the Voltage-Gated Sodium Channel Nav1.7 Contributes to Histaminergic Itch in Mice. (PubMed, ACS Chem Neurosci) - "In the present study, we demonstrated that in the dorsal root ganglion (DRG) neurons from histamine-dependent itch model mice induced by compound 48/80, tetrodotoxin-sensitive (TTX-S) but not TTX-resistant Na currents were activated at more hyperpolarized membrane potentials compared to those on DRG neurons from vehicle-treated mice. Importantly, selective inhibition of Nav1.7 by PF-05089771 significantly relieved the scratching frequency in a histamine-dependent itch model induced by compound 48/80. Taken together, these data suggest that activation of H1 receptors by histamine sensitizes Nav1.7 channels through the PKC pathway in DRG neurons that contributes to histamine-dependent itch."

Journal • Preclinical • Dermatology

The effect of the voltage-gated sodium channel Na1.7 blocker PF-05089771 on cough in the guinea pig. (PubMed, Respir Physiol Neurobiol) - "Compared to vehicle, peroral or inhaled PF-05089771 administration caused about 50-60% inhibition of cough at the doses that did not alter respiratory rate. We conclude that the Na1.7 blocker PF-05089771 inhibits cough in a manner consistent with its electrophysiological effect on airway C-fibre nerve terminals."

Journal • Cough • Pain • Respiratory Diseases

Fast voltage-dependent sodium (Na ) currents are functionally expressed in mouse corpus cavernosum smooth muscle cells. (PubMed, Br J Pharmacol) - "We report, for the first time, a fast voltage-dependent sodium current in mouse CCSM. Stimulation of this current increases the contractility of corpus cavernosum in vitro, suggesting that it may contribute to the mechanisms of detumescence, and potentially serve as a clinically relevant target for pharmaceutical intervention in erectile dysfunction. Further work will be necessary to define its role."

Journal • Preclinical • Erectile Dysfunction

Role of NaV1.7 in Action Potential Conduction along Human Bronchial Vagal Afferent C-fibers. (PubMed, Br J Pharmacol) - "NaV1.7 blockers can prevent action potential conduction in the majority of vagal C-fibers arising from human bronchi. Blockers of NaV1.7 channels may therefore have value in inhibiting the responses to excessive airway C-fiber activation in inflammatory airway disease; responses that include coughing as well as reflex bronchoconstriction and secretions."

Journal • Asthma • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases

Contribution of tetrodotoxin-sensitive voltage-gated sodium channels (Na1) to action potential discharge from mouse esophageal tension mechanoreceptors. (PubMed, Am J Physiol Regul Integr Comp Physiol) - "The combination of PF-05089771 and ICA-121341 inhibited but did not eliminate mechanoreceptor responses. In summary, multiple Na1 subtypes contribute to electrical signaling in esophageal mechanoreceptors. Thus inhibition of individual Na1s would likely have minimal effect on afferent regulation of esophageal motility."

Journal • Preclinical • Gastrointestinal Disorder • Pain

Voltage-gated sodium channels mediating conduction in vagal motor fibers innervating the esophageal striated muscle. (PubMed, Physiol Res) - "Tetrodotoxin (TTX) applied to the vagus nerve completely abolished electrically evoked contractions. The selective NaV1.7 inhibitor PF-05089771 alone partially inhibited contractions and caused a >3-fold rightward shift in the TTX concentration-inhibition curve...We conclude that the action potential conduction in the vagal motor fibers to the esophageal striated muscle in the mouse is mediated by TTX-sensitive voltage gated sodium channels including NaV1.7 and most probably NaV1.6. The role of NaV1.6 is supported by ruling out other TTX-sensitive NaV1s (NaV1.1-1.4) in the NaV1.7-independent conduction."

Journal • Pain

Sensory neuron-derived Na1.7 contributes to dorsal horn neuron excitability. (PubMed, Sci Adv) - "Na1.7 blocker PF05089771 diminished excitability in dorsal horn neurons but had no effect on Na1.7 null mutant mice. These data demonstrate an unsuspected functional role of primary afferent neuron-generated Na1.7 in dorsal horn neurons and an expression pattern that would not be predicted by transcriptomic analysis."

Journal • Pain

Lidocaine binding enhances inhibition of Nav1.7 channels by the sulfonamide PF-05089771. (PubMed, Mol Pharmacol) - "The gating state-mediated interaction between the compounds illustrates a principle applicable to many state-dependent agents. SIGNIFICANCE STATEMENT: The results show that lidocaine enhances the degree and rate of inhibition of Nav1.7 channels by the aryl sulfonamide compound PF-05089771, consistent with state-dependent binding by lidocaine increasing the fraction of channels presenting a high-affinity binding site for PF-05089771 and suggesting that combinations of agents targeted to the pore-region binding site of lidocaine and the external binding site of aryl sulfonamides may have synergistic actions."

Journal • Anesthesia

The stimulus intensity-dependent recruitment of NaV1 subunits in action potential initiation in nerve terminals of vagal C-fibers innervating the esophagus. (PubMed, Am J Physiol Gastrointest Liver Physiol) - "The PF-05089771-insensitive component of the response progressively increased (up to ≈50%) with increasing esophageal distention and was abolished by tetrodotoxin (TTX). However, the response evoked by higher (noxious) levels of esophageal distention has a progressively increasing NaV1.7-independent component that involves multiple TTX-sensitive NaV1s. The stimulus intensity-dependent recruitment of NaV1s may offer novel opportunities for strategic targeting of NaV1 subunits for inhibition of nociceptive signaling in visceral C-fibers."

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