Prof. Simona Collina, University of Pavia; Dr Daniela Rossi, University of Pavia; Dr Annamaria Marra, University of Pavia; Dr Marco Peviani, University of Pavia; Dr Daniela Curti, University of Pavia
University of Pavia
Neuropathic pain (NP) is a chronic debilitating disorder caused by tissue injury and relative damages or an impairment of the nerve pain signaling pathways. There are several causes that induces NP e.g. diabetes, amputation, HIV infection or AIDS and chemotherapy-induced peripheral neurotoxicity (CIPN), a pathologic condition that frequently occurs in cancer patients. All of them are associated with severe, chronic and pharmacologically untreatable pain.
Sigma 1 Receptors (S1Rs) have been strongly correlated to NP, since their inactivation may decrease allodynia or dysesthesia, promoting analgesic effect. Particularly, S1Rs have a crucial role in chronic pain, in virtue of their ability in modulating the activities of genes or proteins (e.g. substance P receptor, NK1R), also involved in NP. Due to the relevance of the unmet clinical need, the novel drug candidates - the patented arylalkanolaminic S1R antagonists (S1RA) - seem to be promising candidates for development.
According to online available reports (www.marketresearchfuture.com), global NP market was $ 5.5 billion in 2017 and it is expected to reach $ 8.1 billion, growing at the Compound Annual Growth Rate (CAGR) of 5.5%. The major driving factor for global NP market is represented by pain associated to cancer (CIPN) and diabetes (diabetic neuropathy). From a geographical perspective, North America and Europe dominate the market, since they count the major number of patients affected by the afore-mentioned pathologies. Accordingly, in these regions the market of NP drugs is expected to increase up to $ USD 2.8 billion within 2023. In this scenario, the novel class of patented S1RAs takes place and could represent an interesting therapeutic opportunity, being NP and CIPN an unmet clinical need.
The hit compound PV-752, showing good binding affinity and selectivity towards S1R (KiS1R= 6.2 nM, KiS2R > 360 nM), was subjected to in vitro preliminary characterization, evidencing that i) it is a potent and selective S1Rs antagonist; ii) it is metabolically stabile after incubation with different biological matrices including liver microsomes and plasma. Importantly, a proof of concept (PoC) was achieved in vivo, where it showed significant antinociceptive activity in in the spinal nerve ligation model (Chung’s model) of severe NP. Of high interest, PV-752 is effective also in an in vivo model of chronic pain (formalin test). From a development perspective, the whole patented compound library has already been prepared, to move one or more candidate molecules, with proper evidence of biological activity and sufficient safety and drug-like properties from preclinical studies into human testing. The most promising compound may represent a valuable pharmacological option to successfully address the current challenges of NP and CIPN treatment, a painful clinical condition affecting millions of subjects worldwide.
European patent has been granted and a US patent application is pending.
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