Abstract

Despite extensive efforts to identify and develop new treatments for pain, more effective and better tolerated therapeutic agents are still needed. Nerve growth factor (NGF), which signals through the TrkA receptor, plays a major role in the development of nociceptive pain as blocking the NGF/TrkA signaling cascade upstream with NGF antibodies has demonstrated significant pain reduction in pre-clinical and clinical settings. However, understanding the role of TrkA in regulating nociceptive pain has been hampered by lack of selective inhibitory tool compounds. To address this issue, we have developed highly selective and potent small molecule allosteric inhibitors of the TrkA receptor. These inhibitors demonstrate good oral exposure in rodents and thus provide a good opportunity to understand the role of TrkA in peripherally mediated nociceptive pain.