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

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

  • J Med Chem. 2018 Aug 9;61(15):6779-6800. doi: 10.1021/acs.jmedchem.8b00633.
Sharan K Bagal 1,  Mark Andrews 2,  Bruce M Bechle 3,  Jianwei Bian 3,  James Bilsland 4,  David C Blakemore 1,  John F Braganza 5,  Peter J Bungay 6,  Matthew S Corbett 3,  Ciaran N Cronin 5,  Jingrong Jean Cui 5,  Rebecca Dias 4,  Neil J Flanagan 4,  Samantha E Greasley 5,  Rachel Grimley 4,  Kim James 7,  Eric Johnson 5,  Linda Kitching 4,  Michelle L Kraus 5,  Indrawan McAlpine 5,  Asako Nagata 5,  Sacha Ninkovic 5,  Kiyoyuki Omoto 1,  Stephanie Scales 5,  Sarah E Skerratt 1,  Jianmin Sun 3,  Michelle Tran-Dubé 5,  Gareth J Waldron 4,  Fen Wang 5,  Joseph S Warmus 3
Affiliations

Affiliations

  • 1 Worldwide Medicinal Chemistry , Pfizer Worldwide R&D U.K. , The Portway Building, Granta Park , Cambridge CB21 6GS , U.K.
  • 2 Pfizer Worldwide R&D U.K. , Sandwich , Kent CT13 9NJ , U.K.
  • 3 Pfizer Worldwide R&D, Groton Laboratories , Eastern Point Road , Groton , Connecticut 06340 , United States.
  • 4 Pfizer Worldwide R&D U.K. , The Portway Building, Granta Park , Cambridge CB21 6GS , U.K.
  • 5 Pfizer Worldwide R&D, La Jolla Laboratories , 10770 Science Center Drive , San Diego , California 92121 , United States.
  • 6 Pharmacokinetics, Dynamics & Metabolism , Pfizer Worldwide R&D U.K. , The Portway Building, Granta Park , Cambridge CB21 6GS , U.K.
  • 7 Peakdale Molecular , Discovery Park House, Ramsgate Road , Sandwich CT13 9ND , U.K.
PMID: 29944371 DOI: 10.1021/acs.jmedchem.8b00633
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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