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

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

Research output: Contribution to journalArticleResearchpeer-review

23 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)10084-10099
Number of pages16
JournalJournal of Medicinal Chemistry
Volume59
Issue number22
DOIs
Publication statusPublished - 23 Nov 2016
Externally publishedYes

Cite this

Skerratt, S. E., Andrews, M., Bagal, S. K., Bilsland, J., Brown, D., Bungay, P. J., ... Waldron, G. (2016). The Discovery of a Potent, Selective, and Peripherally Restricted Pan-Trk Inhibitor (PF-06273340) for the Treatment of Pain. Journal of Medicinal Chemistry, 59(22), 10084-10099. https://doi.org/10.1021/acs.jmedchem.6b00850
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. / The Discovery of a Potent, Selective, and Peripherally Restricted Pan-Trk Inhibitor (PF-06273340) for the Treatment of Pain. In: Journal of Medicinal Chemistry. 2016 ; Vol. 59, No. 22. pp. 10084-10099.
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Skerratt, SE, Andrews, M, Bagal, SK, Bilsland, J, Brown, D, Bungay, PJ, Cole, S, Gibson, KR, Jones, R, Morao, I, Nedderman, A, Omoto, K, Robinson, C, Ryckmans, T, Skinner, K, Stupple, P & Waldron, G 2016, 'The Discovery of a Potent, Selective, and Peripherally Restricted Pan-Trk Inhibitor (PF-06273340) for the Treatment of Pain', Journal of Medicinal Chemistry, vol. 59, no. 22, pp. 10084-10099. https://doi.org/10.1021/acs.jmedchem.6b00850

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.

In: Journal of Medicinal Chemistry, Vol. 59, No. 22, 23.11.2016, p. 10084-10099.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Andrews, Mark

AU - Bagal, Sharan K.

AU - Bilsland, James

AU - Brown, David

AU - Bungay, Peter J.

AU - Cole, Susan

AU - Gibson, Karl R.

AU - Jones, Russell

AU - Morao, Inaki

AU - Nedderman, Angus

AU - Omoto, Kiyoyuki

AU - Robinson, Colin

AU - Ryckmans, Thomas

AU - Skinner, Kimberly

AU - Stupple, Paul

AU - Waldron, Gareth

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