Delving into the Latest Updates on PF-05089771 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

Nav1.7

Action

blockers

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/Sequence

Molecular FormulaC18H12Cl2FN5O3S2

InChIKeyZYSCOUXLBXGGIM-UHFFFAOYSA-N

CAS Registry1235403-62-9

BACKGROUNDAllergic rhinitis (AR) is a common cause of chronic cough, linked to dysregulated airway C- and Aδ-fibres through inflammatory mediators. Despite the limited efficacy of current antitussive therapies, recent studies show that the Na_V1.7 inhibitor can block cough in naïve guinea pigs. This study aimed to analyse the effect of the Na_V1.7 blocker PF-05089771 on cough in guinea pigs with AR.METHODSDunkin Hartley guinea pigs were sensitised and challenged with ovalbumin (OVA). Cough was induced using citric acid aerosol (0.4 M) before nasal challenge (NCH), and then one hour after the 1st, 3rd, and 6th NCH. The OVA-inhibitor group was pre-treated with inhaled Na_V1.7 blocker (PF-05089771, 100 μM) before tussigen inhalation.RESULTSChronic AR increased cough response to citric acid in both males and females. Pre-treatment with Na_V1.7 blocker significantly inhibited cough reflex by ≈ 75 % in males and ≈ 80 % in females without affecting respiratory rate.CONCLUSIONNa_V1.7 blocker inhalation effectively inhibits cough in guinea pigs with AR.

01 Nov 2024·Cell Reports Medicine

Intra-channel bi-epitopic crosslinking unleashes ultrapotent antibodies targeting NaV1.7 for pain alleviation

Article

Author: Zeng, Ziyan ; Fan, Shilong ; Wang, Luyao ; Wu, Mengling ; Zheng, Peiyuan ; Zhang, Yaning ; Ding, Yanchao ; Cao, Qingjuan ; Chen, Hang ; Zhu, Rui ; Ren, Weishuai ; Du, Juanjuan

Crucial for cell activities, ion channels are key drug discovery targets. Although small-molecule and peptide modulators dominate ion channel drug discovery, antibodies are emerging as an alternative modality. However, challenges persist in generating potent antibodies, especially for channels with limited extracellular epitopes. We herein present a bi-epitopic crosslinking strategy to overcome these challenges, focusing on Na_V1.7, a potential analgesic target. Aiming to crosslink two non-overlapping epitopes on voltage-sensing domains II and IV, we construct bispecific antibodies and ligand-antibody conjugates. Enhanced affinity and potency are observed in comparison to the monospecific controls. Among them, a ligand-antibody conjugate (1080-PEG₇-ACDTB) displays a two-orders-of-magnitude improvement in potency (IC₅₀ of 0.06 ± 0.01 nM) and over 1,000-fold selectivity for Na_V1.7. Additionally, this conjugate demonstrates robust analgesic effects in mouse pain models. Our study introduces an approach to developing effective antibodies against Na_V1.7, thereby initiating a promising direction for the advancement of pain therapeutics.

01 Aug 2024·Clinical Pharmacokinetics

Physiologically Based Pharmacokinetic Model of OATP1B Substrates with a Nonlinear Mixed Effect Approach: Estimating Empirical In Vitro-to-In Vivo Scaling Factors

Article

Author: Li, Rui ; Kimoto, Emi ; Varma, Manthena V S ; Tess, David ; Bi, Yi-An

BACKGROUND AND OBJECTIVEPhysiologically based pharmacokinetic (PBPK) models are valuable for translating in vitro absorption, distribution, metabolism, and excretion (ADME) data to predict clinical pharmacokinetics, and can enable discovery and early clinical stages of pharmaceutical research. However, in predicting pharmacokinetics of organic anion transporting polypeptide (OATP) 1B substrates based on in vitro transport and metabolism data, PBPK models typically require additional empirical in vitro-to-in vivo scaling factors (ESFs) in order to accurately recapitulate observed clinical profiles. As model simulation is very sensitive to ESFs, a critical evaluation of ESF estimation is prudent. Previously studies have applied classic 'two-stage' and 'naïve pooled data' approaches in identifying a set of compound independent ESFs. However, the 'two-stage' approach has the parameter identification issue in separately fitting data for individual compounds, while the 'naïve pooled data' approach ignores interstudy variability, leading to potentially biased ESF estimates.METHODSIn this study, we have applied a nonlinear mixed-effect approach in estimating ESF of the PBPK model and incorporated additional data from 86 runs of in vitro uptake assay and 49 clinical studies of 12 training compounds in model development to further enhance the translation of in vitro data to predict the pharmacokinetics of OATP1B substrate drugs. To test predication accuracy of the model, a 'leave-one-out' analysis has been performed.RESULTSThe established model can reasonably describe the clinical observations, with both mean values and interstudy variabilities quantified for ESF and volume of distribution parameters. The mean estimates are largely consistent with values in the previous reports. The interstudy variabilities of these parameters are estimated to be at least 50% (as coefficient of variation). Most compounds can be reasonably predicted in the 'leave-one-out' analysis.CONCLUSIONThis study improves the confidence in predicting the pharmacokinetics of OATP1B substrates in individual studies of small sample sizes, and quantifies the variability associated with the prediction.

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.	-
Toothache	Preclinical	United States	Icagen, Inc.	-
Diabetic peripheral neuropathy	Discovery	United States	Pfizer Inc.	10 Nov 2014
Erythromelalgia	Discovery	United States	Pfizer Inc.	22 Oct 2012
Osteoarthritis, Knee	Discovery	Belgium	Pfizer Inc.	01 Jan 2012
Pain, Postoperative	Discovery	United States	Pfizer Inc.	12 Dec 2011
Pain	Discovery	United Kingdom	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)	mhcuxxyzyt(ixpprlbrnc) = bxxvkfocnl kashdtseys (kkfpsztirm, nxeaxmoynf - fialwcqxqy) View more	-	01 Jun 2018
				Placebo+PF-05089771 (PF-05089771 450 mg)	mhcuxxyzyt(ixpprlbrnc) = ycwfdjbngy kashdtseys (kkfpsztirm, hckingmcln - bnjhktjhgp) View more