Discovery of Allosteric, Potent, Subtype Selective, and Peripherally Restricted TrkA Kinase Inhibitors

Tropomyosin receptor kinases (TrkA,
TrkB, TrkC) are activated by
hormones of the neurotrophin family: nerve growth factor (NGF), brain
derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin
4 (NT4). Moreover, the NGF antibody tanezumab has provided clinical
proof of concept for inhibition of the TrkA kinase pathway in pain
leading to significant interest in the development of small molecule
inhibitors of TrkA. However, achieving TrkA subtype selectivity over
TrkB and TrkC via a Type I and Type II inhibitor binding mode has
proven challenging and Type III or Type IV allosteric inhibitors may
present a more promising selectivity design approach. Furthermore,
TrkA inhibitors with minimal brain availability are required to deliver
an appropriate safety profile. Herein, we describe the discovery of
a highly potent, subtype selective, peripherally restricted, efficacious,
and well-tolerated series of allosteric TrkA inhibitors that culminated
in the delivery of candidate quality compound 23.