In Pursuit of an Allosteric Human Tropomyosin Kinase A (TrkA) Inhibitor for Chronic Pain.

Human β-nerve growth factor (β-NGF) and its associated receptor, human tropomyosin receptor kinase A (TrkA), have been demonstrated to be key factors in the perception of pain. However, efficacious small molecule therapies targeting the intracellularly located TrkA kinase have not been explored thoroughly for pain management. Herein, we report the pharmacological properties of a selective TrkA allosteric inhibitor, . was shown to be active against the full length TrkA, showing preferential binding for the inactive kinase, and was confirmed through the X-ray of TrkA··· bound complex. was also found to inhibit β-NGF induced neurite outgrowth in rat PC12 cells. Daily oral administration of improved the joint compression threshold of rats injected intra-articularly with monoiodoacetate over a 14-day period. The efficacy of in a relevant chronic pain model of osteoarthritis coupled with confirmation of target mediation makes allosteric TrkA inhibitors potential candidates for modulating pain.