Delving into the Latest Updates on PF-05089771 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

Nav1.7

Mechanism

Nav1.7 blockers(Sodium channel protein type IX alpha subunit blockers)

Therapeutic Areas

Nervous System Diseases

Active Indication

Neuralgia

Inactive Indication

Diabetic peripheral neuropathyErythromelalgiaOsteoarthritis, Knee+ [2]

Originator Organization

Pfizer Inc.

Active Organization

Pfizer Inc.

Inactive Organization

Icagen, Inc.

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC18H12Cl2FN5O3S2

InChIKeyZYSCOUXLBXGGIM-UHFFFAOYSA-N

CAS Registry1235403-62-9

AbstractNaV1.7 plays a crucial role in inducing and conducting action potentials in pain‐transducing sensory nociceptor fibres, suggesting that NaV1.7 blockers could be effective non‐opioid analgesics. While SCN9A is expressed in both sensory and autonomic neurons, its functional role in the autonomic system remains less established. Our single neuron rt‐PCR analysis revealed that 82% of sympathetic neurons isolated from guinea‐pig stellate ganglia expressed NaV1.7 mRNA, with NaV1.3 being the only other tetrodotoxin‐sensitive channel expressed in approximately 50% of neurons. We investigated the role of NaV1.7 in conducting action potentials in postganglionic sympathetic nerves and in the sympathetic adrenergic contractions of blood vessels using selective NaV1.7 inhibitors. Two highly selective NaV1.7 blockers, GNE8493 and PF 05089771, significantly inhibited postganglionic compound action potentials by approximately 70% (P < 0.01), with residual activity being blocked by the NaV1.3 inhibitor, ICA 121431. 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. Our results demonstrated that blocking NaV1.7 with GNE8493, PF 05089771, or ST2262 abolished or strongly inhibited sympathetic adrenergic responses in guinea‐pigs and human vascular smooth muscle. These findings support the hypothesis that pharmacologically inhibiting NaV1.7 could potentially reduce sympathetic and parasympathetic function in specific vascular beds and airways.

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Key points

82% of sympathetic neurons isolated from the stellate ganglion predominantly express NaV1.7 mRNA.

NaV1.7 blockers inhibit action potential conduction in postganglionic sympathetic nerves.

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.

01 Sep 2023·Journal of Neurophysiology

Action potential conduction in the mouse and rat vagus nerve is dependent on multiple voltage-gated sodium channels (Na_V1s)

Article

Author: Pavelkova, Nikoleta ; Taylor-Clark, Thomas E. ; Murphy, Claire M. ; Kollarik, Marian ; Nair, Sanjay S.

Distinct NaV1 channels are involved in action potential (AP) initiation and conduction from afferent terminals within specific organs. Here, we have identified the NaV1 necessary for AP conduction in the entire murine and rat vagus nerve. We show TTX-sensitive channels are essential for all AP conduction, predominantly NaV1.7 with NaV1.2 and NaV1.6 playing lesser roles depending on the species and fiber type. In addition, we show that NaV1.8 is also essential for most axonal AP conduction.

01 Jun 2023·Respiratory Physiology & Neurobiology

Influence of combined voltage-gated sodium channel NaV1.7 and NaV1.8 inhibitors on cough in a guinea pig model

Article

Author: Plevkova, Jana ; Jakusova, Janka ; Melegova, Jana ; Buday, Tomas ; Brozmanova, Mariana

Pathological excessive cough is a serious clinical problem in many patients. It is no doubt that an increased activation and sensitization of airway vagal C-fibres in disease stems from dysregulation of the neural pathways that control cough. Due to the limited efficacy and unwanted side effects of current antitussives, there is a continual demand for the development of a novel more effective antitussive. Since voltage-gated sodium channels (Na_Vs) are absolutely required for action potentials initiation and conduction irrespective of the stimulus, Na_Vs became a promising and attractive neural target. Current studies establish that Na_V1.7 and Na_V1.8 inhibitors have the potential to suppress cough. In this study, we demonstrated that inhaled aerosol of Na_V1.7 inhibitor PF-05089771 (10 μM) and Na_V1.8 inhibitor A-803467 (1 mM) 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 Na_V1.7 and Na_V1.8 may present promising therapeutic targets for antitussive therapy.

100 Deals associated with PF-05089771

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External Link

KEGG	Wiki	ATC	Drug Bank
-	PF-05089771	-	DB14856

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Neuralgia	Phase 2	-	Pfizer Inc.	-
Diabetic peripheral neuropathy	Phase 1	US	Pfizer Inc.	10 Nov 2014
Erythromelalgia	Phase 1	US	Pfizer Inc.	22 Oct 2012
Osteoarthritis, Knee	Phase 1	BE	Pfizer Inc.	01 Jan 2012
Pain, Postoperative	Phase 1	US	Pfizer Inc.	12 Dec 2011
Pain	Phase 1	GB	Icagen, Inc.	-
Toothache	Phase 1	US	Icagen, Inc.	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01529346 (CTgov)	Phase 2	Pain, Postoperative	235	Placebo+PF-05089771 (PF-05089771 150 mg)	lfbmsxhaxh(ngdipxqbsf) = mdufknddgn belkrkzlcy (anqnllbock, hldlozhduv - magodquryk) View more	-	01 Jun 2018
				Placebo+PF-05089771 (PF-05089771 450 mg)	lfbmsxhaxh(ngdipxqbsf) = qfmvqifhhg belkrkzlcy (anqnllbock, ywyqkrnmjb - rvhhegagdp) View more