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

Bagal SK, Andrews M, Bechle BM, Bian J, Bilsland J, Blakemore DC, Braganza JF, Bungay PJ, Corbett MS, Cronin CN, Cui JJ, Dias R, Flanagan NJ, Greasley SE, Grimley R, James K, Johnson E, Kitching L, Kraus ML, McAlpine I, Nagata A, Ninkovic S, Omoto K, Scales S, Skerratt SE, Sun J, Tran-Dubé M, Waldron GJ, Wang F, Warmus JS
J Med Chem 61 6779-6800 (2018)
Related entries: 6dkg, 6dki, 6dkw

Cited: 10 times
EuropePMC logo PMID: 29944371

Abstract

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.

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  2. Peripheral Voltage-Gated Cation Channels in Neuropathic Pain and Their Potential as Therapeutic Targets. Alles SRA, Smith PA. Front Pain Res (Lausanne) 2 750583 (2021)
  3. Recent Advances in Pain Management: Relevant Protein Kinases and Their Inhibitors. Giraud F, Pereira E, Anizon F, Moreau P. Molecules 26 2696 (2021)
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