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Steroids as allosteric modulators of NMDAR for neuropathic pain treatment

Dr Eva Kudová, Institute of Organic Chemistry and Biochemistry;  Prof. Ladislav Vyklický, Institute of Physiology (FGU);  Dr Jiří Paleček, Institute of Physiology (FGU)

IOCB Tech


Challenge

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. The main classes of drugs used in the treatment of NP have traditionally consisted of antidepressants, anticonvulsants, opioid analgesics, and topical analgesics. Although many of those available drugs offer some degree of efficacy in terms of pain relief, there still remains vast room for improvement in efficacy, safety, drug delivery, and dosing convenience.


Technology

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 have demonstrated neuroprotective activity in a number of clinical and preclinical studies, their current therapeutic use is, however, limited by their unacceptable side-effect profile. NMDARs are abundant and ubiquitously distributed throughout the CNS and general 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. On the other hand, 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.

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.


Commercial Opportunity

Market size 2017 is about 3 bn USD, CAGR 3%. Therapeutics with completely new mode of action and high efficacy can easily acquire 30% of the market.


Development Status

Drug discovery, non-GLP pre-clinical faze.


Patent Situation

EP 3186267 (A), US 2017/0240588, CA 2957906, AU 2015309371, JP 2017-511948


Further Reading

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.


 

Steroids as allosteric modulators of NMDAR for neuropathic pain treatment
Steroids as allosteric modulators of NMDAR for neuropathic pain treatment

Paclitaxel-Induced Neuropathic Pain model in rats. MS-225 increases the pain threshold in comparison to gabapentin, with a faster onset and more pronounced effect in pain threshold