Design, synthesis and SAR of small molecules acting on pain pathways

Pain is a pathological disease that constitutes one of the most important problems of public health. Epidemiological studies showed that about 20% of the Europe population is affected by moderate or chronic pain. This data highlighted the gigantic impact of this problem not only in the suffering people but also in term of costs for public health. The classes of drugs most used today in the treatment of pain are NSAIDs and opioids. Unfortunately, both have important side effects specially when used in chronic treatment. Therefore, the research of new drugs which exploiting new targets that have an analgesic effect without the side effects is important. This thesis describes the design, synthesis and biological activity of compounds which have potential analgesic activity by their action on three different pathways involved in pain information transmission. 1. The first class of compounds, are amide derivatives of the principal NSAIDs or correlated molecules, they are designed to be able to interact with the endocannabinoid system. In particular, described compounds were designed and tested as inhibitors of FAAH, the principal enzyme involved on the metabolization of endocannabinoids. The aim was to cause an increase of the endocannabinoids concentration which leads to analgesic effect by the potentiation of the endocannabinoid tone. Some of the studied compounds showed inhibitory activity against FAAH at micromolar to nanomolar concentrations. 2. The second class of compounds were designed to interact with prokineticin system. Numerous studies highlighted the involvement of this system in different physiological processes including nociception. Activation of these receptors on the neurons on the pain pathways produces hyperalgesic effects. Therefore, the development of prokineticin receptor antagonists could be a new strategy for pain therapy. Compounds described in this thesis are endowed with triazinedione structure. A new synthetic procedure was set up allowing yields up to 50% higher than reported for analogue compounds. The triazinediones showed in vivo Design, synthesis and SAR of small molecules acting on pain pathways analgesic activity at picomolar concentrations and demonstrated antagonistic activity on prokineticin receptors. 3. The third target on which the compounds reported in this thesis act is the channel-receptor TRPV1, which is an important component of pain information transmission pathways. TRPV1 opening causes an influx of positive ions inside the cell that lead to its depolarization and consequent propagation of the information on the upper levels. In this case then the block of this channel with antagonist or molecules that cause receptor desensitization could result in an analgesic effect. The above mentioned triazinediones demonstrated a modulatory activity component against TRPV1 receptor, which may explain at least in part their in vivo analgesic activity.