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

No abstract is available for this paper.

• Publication year

  2016

• Venue

  Journal of Medicinal Chemistry

• Publication date

  2016-11-04

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1021/ACS.JMEDCHEM.6B00850PMID 27766865
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• The ins and outs of selective kinase inhibitor development.

  2015cited by this paper
• Kinase hinge binding scaffolds and their hydrogen bond patterns.

  2015cited by this paper
• Restricting CNS penetration of drugs to minimise adverse events: role of drug transporters.

  2014cited by this paper
• Exploration of Type II Binding Mode: A Privileged Approach for Kinase Inhibitor Focused Drug Discovery?

  2014cited by this paper
• Interpretable, Probability-Based Confidence Metric for Continuous Quantitative Structure-Activity Relationship Models

  2013cited by this paper
• Why Clinical Modulation of Efflux Transport at the Human Blood–Brain Barrier Is Unlikely: The ITC Evidence‐Based Position

  2013cited by this paper
• Trk B signaling in dopamine 1 receptor neurons regulates food intake and body weight

  2013cited by this paper
• Medicinal chemistry approaches to avoid aldehyde oxidase metabolism.

  2012cited by this paper
• The neurotrophin family of neurotrophic factors: an overview.

  2012cited by this paper
• Anaplastic Lymphoma Kinase Inhibitors for the Treatment of ALK-Positive Cancers

  2012cited by this paper
• Strategies to minimize CNS toxicity: in vitro high-throughput assays and computational modeling

  2012cited by this paper
• TrkA Gene Ablation in Basal Forebrain Results in Dysfunction of the Cholinergic Circuitry

  2012cited by this paper
• Prediction of Nonlinear Intestinal Absorption of CYP3A4 and P-Glycoprotein Substrates from their In Vitro Km Values

  2012cited by this paper
• Full efficacy with no CNS side-effects: unachievable panacea or reality? DMPK considerations in design of drugs with limited brain penetration

  2012cited by this paper
• The crystal structures of TrkA and TrkB suggest key regions for achieving selective inhibition.

  2012cited by this paper
• Proof of concept trial of tanezumab for the treatment of symptoms associated with interstitial cystitis.

  2011cited by this paper
• Chapter 3:The Learning and Evolution of Medicinal Chemistry against Kinase Targets

  2011cited by this paper
• Understanding the Impact of the P-loop Conformation on Kinase Selectivity

  2011cited by this paper
• Long-term open-label study of tanezumab for moderate to severe osteoarthritic knee pain.

  2011cited by this paper
• In situ kinase profiling reveals functionally relevant properties of native kinases.

  2011cited by this paper
• The lighter side of BDNF.

  2011cited by this paper
• Extraction of tacit knowledge from large ADME data sets via pairwise analysis.

  2011cited by this paper
• Efficacy and safety of tanezumab in the treatment of chronic low back pain

  2011cited by this paper
• The discovery and development of analgesics: new mechanisms, new modalities.

  2010cited by this paper
• Membrane transporters in drug development

  2010cited by this paper
• Tanezumab for the treatment of pain from osteoarthritis of the knee.

  2010cited by this paper
• Selectively nonselective kinase inhibition: striking the right balance.

  2010cited by this paper
• Aldehyde oxidase: an enzyme of emerging importance in drug discovery.

  2010cited by this paper
• TrkB signalling pathways in LTP and learning

  2009cited by this paper
• Trk kinase inhibitors as new treatments for cancer and pain

  2009cited by this paper
• A quantitative analysis of kinase inhibitor selectivity

  2008cited by this paper
• Studies on the mechanism of aldehyde oxidase and xanthine oxidase.

  2008cited by this paper
• Glutamate and Neurotrophic Factors in Neuronal Plasticity and Disease

  2008cited by this paper
• Early evaluation of compound QT prolongation effects: a predictive 384-well fluorescence polarization binding assay for measuring hERG blockade.

  2007cited by this paper
• Functional interrogation of the kinome using nucleotide acyl phosphates.

  2007cited by this paper
• Gini coefficient: a new way to express selectivity of kinase inhibitors against a family of kinases.

  2007cited by this paper
• The influence of drug-like concepts on decision-making in medicinal chemistry

  2007cited by this paper
• Novel class of pain drugs based on antagonism of NGF.

  2006cited by this paper
• Rational design of inhibitors that bind to inactive kinase conformations

  2006cited by this paper
• RELATIONSHIP BETWEEN EXPOSURE AND NONSPECIFIC BINDING OF THIRTY-THREE CENTRAL NERVOUS SYSTEM DRUGS IN MICE

  2005cited by this paper
• Features of selective kinase inhibitors.

  2005cited by this paper
• Clinical Pharmacokinetics of Imatinib

  2005cited by this paper
• In vivo function of NGF/TrkA signaling in the cholinergic neurons of the murine basal forebrain

  2005cited by this paper
• Structural Basis for the Autoinhibition and STI-571 Inhibition of c-Kit Tyrosine Kinase*

  2004cited by this paper
• The specificities of protein kinase inhibitors: an update.

  2003cited by this paper
• Protein kinases — the major drug targets of the twenty-first century?

  2002cited by this paper
• Inhibition of p38 MAP kinase by utilizing a novel allosteric binding site

  2002cited by this paper
• Brain-Derived Neurotrophic Factor (BDNF) Is Upregulated and Associated with Pain in Chronic Pancreatitis

  2001cited by this paper
• Structural mechanism for STI-571 inhibition of abelson tyrosine kinase.

  2000cited by this paper

• Molecular determinants of signal transduction in tropomyosin receptor kinases

  2025cites this paper
• Discovery of imidazo[1,2-b]pyridazine derivatives as potent TRK inhibitors for overcoming multiple resistant mutants

  2025cites this paper
• Design of new small molecules derived from indolin-2-one as potent TRKs inhibitors using a computer-aided drug design approach

  2024cites this paper
• Recent advancement in pyrrolidine moiety for the management of cancer: A review

  2024cites this paper
• Design, Synthesis, and Biological and in silico Evaluation of Novel Indazole-pyridine Hybrids for the Treatment of Breast Cancer.

  2024cites this paper
• The tyrosine phosphatases LAR and PTPRδ act as receptors of the nidogen-tetanus toxin complex

  2024cites this paper
• Discovery of novel indazole derivatives as second-generation TRK inhibitors.

  2024cites this paper
• Discovery and Hit to Lead Optimization of Macrocyclic Peptides as Novel Tropomyosin Receptor Kinase A Antagonists.

  2024cites this paper
• Brain-Derived Neurotrophic Factor, Nociception, and Pain

  2024cites this paper
• Design, synthesis and evaluate of indazolylaminoquinazoline derivatives as potent Tropomyosin receptor kinase (TRK) inhibitors.

  2024cites this paper
• Harnessing the necessary nitrogen atom in chemical biology and drug discovery

  2023cites this paper
• Challenges and Opportunities for In Vitro–In Vivo Extrapolation of Aldehyde Oxidase-Mediated Clearance: Toward a Roadmap for Quantitative Translation

  2023cites this paper
• Efferent axons in the zebrafish lateral line degenerate following sensory hair cell ablation.

  2023cites this paper
• A novel c-Met/TRK inhibitor 1D228 efficiently inhibits tumor growth by targeting angiogenesis and tumor cell proliferation

  2023cites this paper
• Design, synthesis and biological evaluation of novel indolin-2-one derivatives as potent second-generation TRKs inhibitors.

  2023cites this paper
• Discovery of novel 3-(1H-pyrazol-4-yl)-1H-indazole derivatives as potent type II TRK inhibitors against acquired resistance.

  2023cites this paper
• The tyrosine phosphatase LAR acts as a receptor of the nidogen-tetanus toxin complex

  2023cites this paper
• Boosting peripheral BDNF rescues impaired in vivo axonal transport in CMT2D mice

  2023influential citation
• Biocompatible Macroion/Growth Factor Assemblies for Medical Applications

  2023cites this paper
• A BDNF-TrkB autocrine loop enhances senescent cell viability

  2022cites this paper
• Research Progress on Small Molecules Inhibitors Targeting TRK Kinases.

  2022cites this paper
• Design, synthesis and anti-tumor efficacy of novel phenyl thiazole/triazole derivatives as selective TrkA inhibitors.

  2022cites this paper
• Drug clearance by aldehyde oxidase: can we avoid clinical failure?

  2022cites this paper
• Structural Optimization and Structure-Activity Relationship Studies of 6,6-Dimethyl-4-(phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one Derivatives as A New Class of Potent Inhibitors of Pan-Trk and Their Drug-Resistant Mutants.

  2022cites this paper
• Discovery of a Novel Template, 7-Substituted 7-Deaza-4′-Thioadenosine Derivatives as Multi-Kinase Inhibitors

  2021cites this paper
• Recent Advances in Pain Management: Relevant Protein Kinases and Their Inhibitors

  2021cites this paper
• Crystal Structures of Drug-Metabolizing CYPs.

  2021cites this paper
• Discovery of Next-Generation Tropomyosin Receptor Kinase (TRK) Inhibitors for Combatting Resistance Associated with Protein Mutation

  2021influential citation
• Rational design of allosteric modulators: Challenges and successes

  2021cites this paper
• Discovery of Next-Generation Tropomyosin Receptor Kinase Inhibitors for Combating Multiple Resistance Associated with Protein Mutation.

  2021cites this paper
• In Pursuit of an Allosteric Human Tropomyosin Kinase A (hTrkA) Inhibitor for Chronic Pain.

  2021cites this paper
• Small-Molecule Kinase Inhibitors for the Treatment of Nononcologic Diseases.

  2021cites this paper
• Discovery of pyrazolo-thieno[3,2-d]pyrimidinylamino-phenyl acetamides as type-II pan-tropomyosin receptor kinase (TRK) inhibitors: Design, synthesis, and biological evaluation.

  2021cites this paper
• Novel Approaches, Drug Candidates, and Targets in Pain Drug Discovery.

  2021cites this paper
• Impact of the Protein Data Bank on antineoplastic approvals.

  2020cites this paper
• High-Throughput Screening For The Discovery Of Enzyme Inhibitors.

  2020cites this paper
• Development of small-molecule tropomyosin receptor kinase (TRK) inhibitors for NTRK fusion cancers

  2020influential citation
• Lead optimization of 8-(methylamino)-2-oxo-1,2-dihydroquinolines as bacterial type II topoisomerase inhibitors.

  2020cites this paper
• The therapeutic potential of PROTACs

  2020cites this paper
• Interplay of BDNF and GDNF in the Mature Spinal Somatosensory System and Its Potential Therapeutic Relevance

  2020cites this paper
• Synthetic inhibitor leads of human tropomyosin receptor kinase A (hTrkA).

  2020cites this paper
• Discovery of Novel Analgesic Agents Targeting Neuropathic Pain: Computer-Aided Drug Design

  2020cites this paper
• TRK-A IN COMPLEX WITH LIGAND 1

  2020cites this paper
• Efficient radiosynthesis and preclinical evaluation of [18 F]FOMPyD as a PET tracer candidate for TrkB/C receptor imaging.

  2020cites this paper
• Complete Accounts of Integrated Drug Discovery and Development: Recent Examples from the Pharmaceutical Industry Volume 2

  2019cites this paper
• Discovery of Allosteric, Potent, Subtype Selective, and Peripherally Restricted TrkA Kinase Inhibitors.

  2019cites this paper
• Validation of Human MDR1-MDCK and BCRP-MDCK Cell Lines to Improve the Prediction of Brain Penetration.

  2019cites this paper
• Crystal structure of Trk-A in complex with the Pan-Trk Kinase Inhibitor, compound 10e

  2019cites this paper
• Type 2 inhibitor leads of human tropomyosin receptor kinase (hTrkA).

  2019cites this paper
• Lead identification and characterization of hTrkA type 2 inhibitors.

  2019cites this paper
• Discovery and Development of AMG 333: A TRPM8 Antagonist for Migraine

  2019cites this paper
• Rational Design to Large-Scale Synthesis: Development of GSK8175 for the Treatment of Hepatitis C Virus Infection

  2019cites this paper
• The Discovery and Chemical Development of PF-06273340: A Potent, Selective, and Peripherally Restricted Pan-Trk Inhibitor for Pain

  2019cites this paper
• The Discovery of the Nav1.7 Inhibitor GDC-0276 and Development of an Efficient Large-Scale Synthesis

  2019cites this paper
• Discovery and Development of Lorlatinib: A Macrocyclic Inhibitor of EML4-ALK for the Treatment of NSCLC

  2019cites this paper
• Discovery and Development of Non-Covalent, Reversible Bruton’s Tyrosine Kinase Inhibitor Fenebrutinib (GDC-0853)

  2019cites this paper
• From Discovery to Market Readiness: The Research and Development of the β-Sparing Phosphatidylinositol 3-Kinase Inhibitor Taselisib

  2019cites this paper
• Discovery and Development of the First Antibody–Antibiotic Conjugate Linker-Drug

  2019cites this paper
• Synthetic Routes for Venetoclax at Different Stages of Development

  2019cites this paper
• Discovery and Early Development of Small Molecule Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors

  2019cites this paper
• Optimization of an Azaindazole Series of CCR1 Antagonists and Development of a Semicontinuous-Flow Synthesis

  2019cites this paper
• Foreword

  2019cites this paper
• The discovery of novel 3-aryl-indazole derivatives as peripherally restricted pan-Trk inhibitors for the treatment of pain.

  2019cites this paper
• Title, Copyright, Foreword

  2019cites this paper
• Editors’ Biographies

  2019cites this paper
• Analysis of NTRK Alterations in Pan-Cancer Adult and Pediatric Malignancies: Implications for NTRK-Targeted Therapeutics.

  2018cites this paper
• Insights into Current Tropomyosin Receptor Kinase (TRK) Inhibitors: Development and Clinical Application.

  2018cites this paper
• Discovery of Potent, Selective, and Peripherally Restricted Pan-Trk Kinase Inhibitors for the Treatment of Pain.

  2018cites this paper
• Demonstration of an anti‐hyperalgesic effect of a novel pan‐Trk inhibitor PF‐06273340 in a battery of human evoked pain models

  2018cites this paper
• From Cancer to Pain Target by Automated Selectivity Inversion of a Clinical Candidate.

  2018cites this paper
• Mapping the Efficiency and Physicochemical Trajectories of Successful Optimizations.

  2018cites this paper
• Where Do Recent Small Molecule Clinical Development Candidates Come From?

  2018cites this paper
• GZD2202, a novel TrkB inhibitor, suppresses BDNF-mediated proliferation and metastasis in neuroblastoma models

  2018cites this paper
• Sustainable Practices in Medicinal Chemistry Part 2: Green by Design.

  2017cites this paper
• Tropomyosin receptor kinase inhibitors: an updated patent review for 2010-2016 – Part I

  2017cites this paper
• Design and synthesis of a fluorinated quinazoline-based type-II Trk inhibitor as a scaffold for PET radiotracer development.

  2017cites this paper
• A Kinome-Wide Selective Radiolabeled TrkB/C Inhibitor for in Vitro and in Vivo Neuroimaging: Synthesis, Preclinical Evaluation, and First-in-Human.

  2017cites this paper
• Tropomyosin receptor kinase inhibitors: an updated patent review for 2010-2016 – Part II

  2017influential citation
• Structural Basis of Single-Nucleotide Polymorphisms in Cytochrome P450 2C9.

  2017cites this paper
• Discovery of aminocyclohexene analogues as selective and orally bioavailable hNav1.7 inhibitors for analgesia.

  2017cites this paper
• Targeting the Nerve Growth Factor (NGF) Pathway in Drug Discovery. Potential Applications to New Therapies for Chronic Pain.

  2017cites this paper
• Evaluation and Characterization of Trk Kinase Inhibitors for the Treatment of Pain: Reliable Binding Affinity Predictions from Theory and Computation

  2017cites this paper
• R esearch Advance in NGF in Neuropathic Pain and Related Drugs

  year unknowncites this paper