2 research outputs found
Discovery of Potent, Selective, and Peripherally Restricted Pan-Trk Kinase Inhibitors for the Treatment of Pain
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 <b>10b</b>, <b>13b</b>, and <b>19</b>. 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
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 <b>10b</b>, <b>13b</b>, and <b>19</b>. 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