January 20, 2014
Trk inhibitors may do more than treat pain. S. J. Stachel and co-inventors disclose urea derivatives represented generally by formula 1. These compounds are tropomyosin-receptor kinase (Trk) inhibitors that may provide treatments for pain, inflammation, cancer, restenosis, atherosclerosis, psoriasis, thrombosis, and other disorders associated with abnormal activities of Trks.
Trks are high-affinity binding protein kinase receptors. The Trk family comprises three members: TrkA, TrkB, and TrkC. They bind to and mediate signal transduction derived from the neurotrophins. TrkA is activated by nerve growth factor (NGF), TrkB by brain-derived neurotrophic factor (BDNF) and neurotrophin 4–5 (NT-4/5), and TrkC by neurotrophin 3 (NT-3). Trks are implicated in several processes and disorders:
- Interaction between TrkA and NGF is required for the survival of certain peripheral neurons that help mediate pain signaling in pancreatic cancer. Increased TrkA expression correlates with an increased level of pain signaling.
- Increased expression of TrkA and NGF occurs in human osteoarthritis chondrocytes.
- Mouse studies show the expression of TrkA and TrkC receptors in bone-forming areas and the localization of NGF in almost all bone-forming cells in bone-fracture models.
- Neuroblastoma studies show an association between the overexpression, activation, amplification, and/or mutation of Trk and several cancers.
- Modulating the neurotrophin–Trk pathway affects the etiology of neurodegenerative diseases such as multiple sclerosis, Parkinson’s disease, and Alzheimer’s disease.
Trk inhibitors such as the compounds disclosed by the inventors may be useful for treating acute and chronic pain, such as inflammatory pain, neuropathic pain, and pain associated with cancer, surgery, and bone fracture. The therapeutic uses of Trk inhibitors, however, may extend beyond pain therapy; they also may be useful for treating osteoporosis, rheumatoid arthritis, and bone metastases.
Other potential uses of Trk inhibitors are treating 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. They also may be useful for treating cancer, inflammation, neurodegenerative diseases, and certain infectious diseases.
The inventors disclose the structures of 163 examples of formula 1, including compounds 2, 3, and 4. They evaluated the compounds by measuring their ability to inhibit the phosphorylation of a fluorescently labeled peptide substrate by TrkA kinase. IC50 values for the compounds of the invention range from 5 nM to 10 mM. The values for compounds 2, 3, and 4 are given in the table.
(The inventors mention IC50 in the text but report EC50 in the data table.—Ed.) (Merck Sharpe & Dohme [Rahway, NJ]. WIPO Publication 2013176970, Nov. 28, 2013; Ahmed F. Abdel-Magid)
This patent was originally reviewed in ACS Medicinal Chemistry Letters.