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Neurosteroids for Neuropathic Pain Treatment

Neuropathic pain is an indication that currently affects about 8 million people worldwide, with the market size of about $3B and expected growth to $8B in 2026. However, treatments for this indication are lacking, and only 30% of patients will see 30% efficacy from the drugs prescribed.

We have synthetized new steroidal molecules with potent modulatory activity at the N-methyl-D-aspartate receptors (NMDARs). Ample evidence supports the key role of this receptor in the pathophysiology of several neuropsychiatric disorders, including the neuropathic pain. NMDARs antagonists demonstrated neuroprotective activity in a number of clinical and preclinical studies, their current therapeutic use is, however, limited by their unacceptable side-effect profile. Current NMDA antagonists interfere with normal synaptic transmission in several brain areas. Indiscriminate NMDA blockade therefore results in impairment of many CNS functions and has been associated with a wide range of neuropsychiatric adverse effects, including disturbances in cognition, mood, learning and memory.

Our compounds are characterized as use-dependent, voltage-independent NMDAR modulators. They are unique in their preference for extrasynaptic, tonically activated NMDARs, which are hypothesized to play an important role in glutamate-mediated excitotoxicity. This presumed mechanism of action predicts minimal effects on physiological synaptic transmission. In line with this assumption, our compounds have low toxicity and no psychomimetic effects at therapeutic doses. The molecular and functional diversity of the NMDARs offers a possibility for a targeted design of drugs that would be selective for a particular receptor subtype.

Preclinical stage – in vitro and in vivo testing, lead optimization, pharmacokinetics, toxicology.

Vyklicky et al.: Journal of Neuroscience 2016, 36(7):2161-2175. Vyklicky et al.: Scientific Reports 2015,18(5):10935. Kudova et al.: Journal of Medicinal Chemistry 2015,58:5950-5966. Borovska et al.: British Journal of Pharmacology 2012, 166(3):1069-1083.

EP 2,313,424 (04-23-2014), US 8,575,376 ,EP 2,675,821, US 2013338383 , CZ 305733 and PCT/CZ2015/000096.

Institute of Organic Chemistry & Biochemistry of Czech Academy of Sciences (70%) Institute of Physiology of Czech Academy of Sciences (30%)