The Discovery of a Potent, Selective, and Peripherally Restricted Pan-Trk Inhibitor (PF-06273340) for the Treatment of Pain

The
neurotrophin family of growth factors, comprised of nerve growth factor
(NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3),
and neurotrophin 4 (NT4), is implicated in the physiology of chronic
pain. Given the clinical efficacy of anti-NGF monoclonal antibody
(mAb) therapies, there is significant interest in the development
of small molecule modulators of neurotrophin activity. Neurotrophins
signal through the tropomyosin related kinase (Trk) family of tyrosine
kinase receptors, hence Trk kinase inhibition represents a potentially “druggable”
point of intervention. To deliver the safety profile required for
chronic, nonlife threatening pain indications, highly kinase-selective
Trk inhibitors with minimal brain availability are sought. Herein
we describe how the use of SBDD, 2D QSAR models, and matched molecular
pair data in compound design enabled the delivery of the highly potent,
kinase-selective, and peripherally restricted clinical candidate PF-06273340.