6dkw

Publication Abstract from PubMed

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, 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.

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 J, 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-Dube M, Waldron GJ, Wang F, Warmus JS J Med Chem. 2018 Jun 26. doi: 10.1021/acs.jmedchem.8b00633. PMID:29944371^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.