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

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

doi:10.1021/acs.jmedchem.6b00850

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

Journal Article · Fri Oct 21 00:00:00 EDT 2016 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/acs.jmedchem.6b00850· OSTI ID:1440591

Skerratt, Sarah E. ^[1]; Andrews, Mark ^[2]; Bagal, Sharan K. ^[1]; Bilsland, James ^[1]; Brown, David ^[2]; Bungay, Peter J. ^[1]; Cole, Susan ^[2]; Gibson, Karl R. ^[2]; Jones, Russell ^[2]; Morao, Inaki ^[2]; Nedderman, Angus ^[2]; Omoto, Kiyoyuki ^[1]; Robinson, Colin ^[2]; Ryckmans, Thomas ^[2]; Skinner, Kimberly ^[2]; Stupple, Paul ^[2]; Waldron, Gareth ^[1]

Pfizer Global Research & Development, Cambridge (United Kingdom)
Pfizer Global Research & Development, Sandwich (United Kingdom)

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. Furthermore, 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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE

OSTI ID:: 1440591

Journal Information:: Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 22 Vol. 59; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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