Bi-functional FLT3-opioid ligands as more potent and safer analgesic agents – FLT3-MOR

Opioid analgesics remain the most effective drugs for moderate to severe pain, but while their efficacy is undisputed in acute and cancer pain, their efficacy for chronic pain on the long term is insufficient, being partly impaired by the development of analgesic tolerance and paradoxical hyperalgesia, which lead to dose escalation, addiction and a risk of life-threatening respiratory depression. Opioid overdose death rate has now reached more than 100,000 per year in the USA. Opioids are more frequently prescribed in France than previously and opioid-related hospitalizations potentially due to prescription pills dramatically rose. Partners of this consortium have demonstrated the role of the receptor tyrosine kinase FLT3 in the generation and maintenance of neuropathic pain, a condition that arises from nerve damage and that resembles morphine-induced hyperalgesia. They also demonstrated that inhibitors of FLT3 potentiate morphine analgesia in post-surgical pain and reverse morphine tolerance and morphine-induced hyperalgesia in chronic inflammatory pain. Hence, having established the proof-of-concept that FLT3 inhibitor/µ opiate agonist combinations improve morphine treatment, this project is the design of bi-functional compounds that combine FLT3 inhibitor potency and µ opiate agonism in the same molecule, which could provide more potent and safer analgesics. The design of bi-functional compounds will include the screening of a chemical library of FLT3 inhibitors (~600 compounds) and standard medicinal chemistry optimization, up to the identification of compounds suitable for clinical development.