Inhibitors of Tropomyosin-Receptor Kinases (Trk’s): Potential Pain Therapy and More

Abstract

Inventors:Stachel, S. J.; Egbertson, M.; Brnardic, E.; Jones, K.; Sanders, J. M.; Henze, D. A. TrkC is activated by Neurotrophin 3 (NT-3). Trk's are implicated in several processes and disorders: • Studies have shown that the interaction of TrkA and NGF is required for the survival of certain peripheral neurons involved in mediating pain signaling in pancreatic cancer and showed also a correlation between increased expression of TrkA and increased level of pain signaling.• Increased expression of TrkA and NGF was observed in human osteoarthritis chondrocytes.• Mouse studies showed the expression of TrkA and TrkC receptors in the bone forming area and the localization of NGF in almost all bone forming cells of bone fracture models.• Studies on neuroblastoma showed an association between overexpression, activation, amplification, and/or mutation of Trks and several cancers.• Studies have shown that modulation of the neutrophin/Trk pathway has an effect in the etiology of neurodegenerative diseases such as multiple sclerosis, Parkinson's disease and Alzeheimer's disease.Trk inhibitors such as the compounds disclosed in this patent application may potentially be useful in the treatment of multiple types of acute and chronic pain, including inflammatory pain, neuropathic pain, and pain associated with cancer, surgery, and bone fracture. However, the therapeutic implications of Trk inhibitors may extend beyond pain therapy. Trk inhibitors may also be useful in treating osteoporosis, rheumatoid arthritis, and bone metastases. They also show promise in the treatment of inflammatory lung diseases such as asthma, inflammatory bowel diseases, such as ulcerative colitis and Chron's disease, and inflammatory skin diseases, such as atopic dermatitis, eczema, and psoriasis. The Trk inhibitors may also be useful in the treatment of cancer, inflammation, neurodegenerative diseases, and certain infectious diseases. Important Compound Classes: