Delving into the Latest Updates on PF-06273340 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

PF 6273340, PF-6273340

Target

NTRK

Mechanism

NTRK inhibitors(Neurotrophic tyrosine kinase receptor inhibitors)

Therapeutic Areas

Nervous System Diseases

Active Indication-

Inactive Indication

Pain

Originator Organization

Pfizer Inc.

Active Organization-

Inactive Organization

Pfizer Inc.

Drug Highest PhasePendingPhase 1

First Approval Date-

Regulation-

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Structure

Molecular FormulaC23H22ClN7O3

InChIKeyBPIWZDNVMQQBQX-UHFFFAOYSA-N

CAS Registry1402438-74-7

A Phase 1, Open Label, Randomized, Single Dose, 5 Period Crossover Relative Bioavailability Study In Healthy Volunteers Evaluating Spray Dried Dispersion (SDD) Immediate Release (IR) PF-06273340 Tablet, Two SDD Modified Release (MR) Matrix Tablets In Comparison With PF-06273340 Oral Solution, Including Preliminary Assessment Of Food Effect

The primary purpose of this study is to estimate the relative bioavailability and food effect of PF-06273340 tablets.

Start Date01 Nov 2012

Sponsor / Collaborator

Pfizer Inc.

100 Clinical Results associated with PF-06273340

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100 Translational Medicine associated with PF-06273340

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100 Patents (Medical) associated with PF-06273340

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3

Literatures (Medical) associated with PF-06273340

09 Aug 2018·Journal of medicinal chemistryQ1 · MEDICINE

Discovery of Potent, Selective, and Peripherally Restricted Pan-Trk Kinase Inhibitors for the Treatment of Pain

Q1 · MEDICINE

Article

Author: Flanagan, Neil J. ; Kitching, Linda ; Bungay, Peter J. ; Sun, Jianmin ; Andrews, Mark ; James, Kim ; Grimley, Rachel ; Scales, Stephanie ; Waldron, Gareth J. ; Greasley, Samantha E. ; Bagal, Sharan K. ; Tran-Dubé, Michelle ; Braganza, John F. ; Bechle, Bruce M. ; Johnson, Eric ; McAlpine, Indrawan ; Nagata, Asako ; Omoto, Kiyoyuki ; Warmus, Joseph S. ; Kraus, Michelle L. ; Blakemore, David C. ; Bilsland, James ; Cui, Jingrong Jean ; Dias, Rebecca ; Ninkovic, Sacha ; Bian, Jianwei ; Corbett, Matthew S. ; Cronin, Ciaran N. ; Skerratt, Sarah E. ; Wang, Fen

Hormones of the neurotrophin family, nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4), are known to activate the family of Tropomyosin receptor kinases (TrkA, TrkB, and TrkC). Moreover, inhibition of the TrkA kinase pathway in pain has been clinically validated by the NGF antibody tanezumab, leading to significant interest in the development of small molecule inhibitors of TrkA. Furthermore, Trk inhibitors having an acceptable safety profile will require minimal brain availability. Herein, we discuss the discovery of two potent, selective, peripherally restricted, efficacious, and well-tolerated series of pan-Trk inhibitors which successfully delivered three candidate quality compounds 10b, 13b, and 19. All three compounds are predicted to possess low metabolic clearance in human that does not proceed via aldehyde oxidase-catalyzed reactions, thus addressing the potential clearance prediction liability associated with our current pan-Trk development candidate PF-06273340.

01 Feb 2018·British journal of clinical pharmacologyQ2 · MEDICINE

Demonstration of an anti‐hyperalgesic effect of a novel pan‐Trk inhibitor PF‐06273340 in a battery of human evoked pain models

Q2 · MEDICINE

Article

Author: Groeneveld, Geert Jan ; Gorman, Donal ; Hay, Justin L. ; Loudon, Peter ; Siebenga, Pieter ; Butt, Richard P. ; van Amerongen, Guido ; Dua, Pinky ; Gore, Katrina

Aim:

Inhibitors of nerve growth factor (NGF) reduce pain in several chronic pain indications. NGF signals through tyrosine kinase receptors of the tropomyosin‐related kinase (Trk) family and the unrelated p75 receptor. PF‐06273340 is a small molecule inhibitor of Trks A, B and C that reduces pain in nonclinical models, and the present study aimed to investigate the pharmacodynamics of this first‐in‐class molecule in humans.

Methods:

A randomized, double‐blind, single‐dose, placebo‐ and active‐controlled five‐period crossover study was conducted in healthy human subjects (NCT02260947). Subjects received five treatments: PF‐06273340 50 mg, PF‐06273340 400 mg, pregabalin 300 mg, ibuprofen 600 mg and placebo. The five primary endpoints were the pain detection threshold for the thermal pain tests and the pain tolerance threshold for the cold pressor, electrical stair and pressure pain tests. The trial had predefined decision rules based on 95% confidence that the PF‐06273340 effect was better than that of placebo.

Results:

Twenty subjects entered the study, with 18 completing all five periods. The high dose of PF‐06273340 met the decision rules on the ultraviolet (UV) B skin thermal pain endpoint [least squares (LS) mean vs. placebo: 1.13, 95% confidence interval: 0.64–1.61], but not on the other four primary endpoints. The low dose did not meet the decision criteria for any of the five primary endpoints. Pregabalin (cold pressor and electrical stair tests) and ibuprofen (UVB thermal pain) showed significant analgesic effects on expected endpoints.

Conclusions:

The study demonstrated, for the first time, the translation of nonclinical effects into man in an inflammatory pain analgesic pharmacodynamic endpoint using a pan‐Trk inhibitor.

23 Nov 2016·Journal of medicinal chemistryQ1 · MEDICINE

The Discovery of a Potent, Selective, and Peripherally Restricted Pan-Trk Inhibitor (PF-06273340) for the Treatment of Pain

Q1 · MEDICINE

Article

Author: Brown, David ; Robinson, Colin ; Omoto, Kiyoyuki ; Bilsland, James ; Waldron, Gareth ; Bungay, Peter J. ; Morao, Inaki ; Andrews, Mark ; Gibson, Karl R ; Skerratt, Sarah E. ; Bagal, Sharan K. ; Cole, Susan ; Skinner, Kimberly ; Ryckmans, Thomas ; Jones, Russell ; Stupple, Paul ; Nedderman, Angus

The neurotrophin family of growth factors, comprised of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4), is implicated in the physiology of chronic pain. Given the clinical efficacy of anti-NGF monoclonal antibody (mAb) therapies, there is significant interest in the development of small molecule modulators of neurotrophin activity. Neurotrophins signal through the tropomyosin related kinase (Trk) family of tyrosine kinase receptors, hence Trk kinase inhibition represents a potentially "druggable" point of intervention. To deliver the safety profile required for chronic, nonlife threatening pain indications, highly kinase-selective Trk inhibitors with minimal brain availability are sought. Herein we describe how the use of SBDD, 2D QSAR models, and matched molecular pair data in compound design enabled the delivery of the highly potent, kinase-selective, and peripherally restricted clinical candidate PF-06273340.

100 Deals associated with PF-06273340

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