PF-05089771(PF-05089771) - 药物靶点：Nav1.7_在研适应症：神经痛_专利_临床

概要

基本信息

药物类型

小分子化药

别名

靶点

Nav1.7

作用机制

Nav1.7阻滞剂(IX型钠通道蛋白α亚基阻滞剂)

治疗领域

神经系统疾病

在研适应症

神经痛

非在研适应症

糖尿病周围神经病变红斑性肢痛症膝关节炎+ [2]

原研机构

Pfizer Inc.

在研机构

Pfizer Inc.

非在研机构

Icagen, Inc.

最高研发阶段临床2期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

结构

分子式C18H12Cl2FN5O3S2

InChIKeyZYSCOUXLBXGGIM-UHFFFAOYSA-N

CAS号1235403-62-9

关联

14

项与 PF-05089771 相关的临床试验

NCT05935280 / Completed早期临床1期IIT

Human Cold Pain - a Single-group, Randomized, Placebo-controlled, Adaptive, Factorial Crossover Trial

Animal studies suggest that the transient receptor potential ion channels TRPM8 and TRPA1 are cold sensors and that sodium channels Nav1.8 and Nav1.7 are essential for detecting pain induced by cold temperatures. This study aims to validate these findings in humans.

开始日期2023-07-07

申办/合作机构

Medical University of Vienna

NCT02349607 / Completed临床1期

A Double Blind, Double Dummy, Randomized, Placebo-controlled, 5 Period Cross-over Study To Examine The Effect Of Pf-05089771 Alone And In Combination With Pregabalin On Evoked Pain Endpoints In Healthy Volunteers Using Pregabalin And Ibuprofen As Positive Controls

This study will examine the activity of PF-05089771 and pregabalin, alone and in combination on a panel of evoked pain tests carried out from 0.5 to 10 hours following oral dosing in healthy male subjects

开始日期2015-01-01

申办/合作机构

Pfizer Inc.

NCT02215252 / Completed临床2期

A Randomized Double Blind Placebo And Active Controlled Parallel Group Phase 2 Study To Evaluate PF-05089771 As A Monotherapy And As An Add-on To Pregabalin For The Treatment Of Painful Diabetic Peripheral Neuropathy

The purpose of this study is to evaluate the efficacy and safety of PF-05089771 as a monotherapy and as an add-on to pregabalin for the treatment of painful diabetic peripheral neuropathy (DPN)

开始日期2014-11-10

申办/合作机构

Pfizer Inc.

100 项与 PF-05089771 相关的临床结果

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100 项与 PF-05089771 相关的转化医学

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100 项与 PF-05089771 相关的专利（医药）

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23

项与 PF-05089771 相关的文献（医药）

2024-07-01·The Journal of Physiology

Role of Na_V1.7 in postganglionic sympathetic nerve function in human and guinea‐pig arteries

Article

作者: Zabka, Tanja S ; Undem, Bradley J ; Meeker, Sonya ; Hackos, David ; Ru, Fei ; Tran, Minh ; Kim, Joyce S

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.

image

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.

2023-09-01·Journal of Neurophysiology

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

Article

作者: 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.

2023-06-01·Respiratory Physiology & Neurobiology

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

Article

作者: 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 项与 PF-05089771 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	PF-05089771	-	DB14856

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
神经痛	临床2期	-	Pfizer Inc.	-
糖尿病周围神经病变	临床1期	美国	Pfizer Inc.	2014-11-10
红斑性肢痛症	临床1期	美国	Pfizer Inc.	2012-10-22
膝关节炎	临床1期	比利时	Pfizer Inc.	2012-01-01
术后疼痛	临床1期	美国	Pfizer Inc.	2011-12-12
疼痛	临床1期	英国	Icagen, Inc.	-
牙痛	临床1期	美国	Icagen, Inc.	-

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT01529346 (CTgov)	临床2期	术后疼痛	235	Placebo+PF-05089771 (PF-05089771 150 mg)	鬱簾糧餘鏇獵繭鹽壓製(網簾鹽鏇網蓋積廠獵齋) = 窪艱壓壓淵醖積廠醖膚築鑰糧艱網網醖膚鹽觸 (蓋築夢顧廠鹹選糧觸築, 構艱遞蓋鏇衊網艱膚餘 ~ 鹹獵艱築衊壓膚選遞餘) 更多	-	2018-06-01
				Placebo+PF-05089771 (PF-05089771 450 mg)	鬱簾糧餘鏇獵繭鹽壓製(網簾鹽鏇網蓋積廠獵齋) = 餘蓋範選艱築壓廠壓衊築鑰糧艱網網醖膚鹽觸 (蓋築夢顧廠鹹選糧觸築, 築膚積範憲齋築憲鬱襯 ~ 遞獵製艱艱顧窪膚壓糧) 更多