Neurosteroids in Neuropathic Pain Treatment
Active

Potent CNS therapeutics – SMART Steroids

Eva Kudová (PI), Jiří Paleček, Jan Jakubík

Challenge

Searching for novel drugs potentially useful for therapy of CNS damage belongs to the most investigated topics in contemporary pharmacology and neuroscience. The proposed project is based on the study of biological properties of newly developed 3αC substituted derivatives of pregnanolone and the evaluation of their pharmacotherapeutic potential.

The current medical treatment of the Neuropathic Pain relies on the ion channel blockers (Gabapentin, Pregabalin) or the serotonin up-take blockers (Duloxetine) or the NMDA antagonists (Memantine, Dextromethorphan). Since direct antagonists or agonists or channel blockers can also severely influence physiological functions, they do have serious adverse side effects during the treatment. Our approach is focused on the allosteric modulation of the neuro-receptors which is milder and just changes the sensitivity of the neuro-receptors to endogenous neurotransmitters or agonists.

Technology

The new proprietary steroids have proven their efficacy in increasing the reaction threshold to mechanical and thermal stimuli in six different animal models in the rat. They act as positive allosteric modulators of opioid and muscarinic receptors with various activity profiles on individual receptor subtypes.

 

The development candidate MS-225 shows good efficacy at doses of 1-3 mg/kg in comparison to the positive control by Gabapentin at 50-100 mg/kg. There were no obvious adverse effects observed up to 10 mg/kg. The MS-225 is bioavailable after p.o. administration and penetrates the BBB. However, its pharmacologic properties have to be optimized as the absolute bioavailability ranges at 1%.

Commercial Opportunity

The technology is offered for co-development and licensing.

Development Status

Preclinical stage, in vitro and in vivo testing, lead optimization, toxicology

Patent Situation

EP 2,313,424 (04-23-2014), US 8,575,376 (11-05-2013),EP 2,675,821 (07-24-2013), US 2013338383 (08-08-2013), CZ 305733 and PCT/CZ2015/000096

IP owners

  • Institute of Organic Chemistry and Biochemistry AS CR, v.v.i.
  • Institute of PhysiologyAS CR, v.v.i.

Further Reading

  1. Kumar A., Kaur H., Singh A.: Neuropathic Pain models caused by damage to central or peripheral nervous system. Pharm. Rep. 2018, 70(2), 206-216.
  2. O´Connor A.B., Dworkin R.H.: Treatment of neuropathic pain. Am. J. Med. 2009, 122(10 Suppl), S22-32.
  3. Trivedi M.S., Hershman D.L., Crew K.D.: Management of Chemotheraphy-Induced Peripheral Neuropathy. Am. J. Hematol. Oncol. 2015, 11(1).
  4. Kudova E., Chodounska H., Kapras V., Vyklicky L., Vales K., Jahn U.: Amphiphilic compounds with neuroprotective properties. EP3186267 A, EP3260462 A, US 2017/0240588, AU 2015309371, CA 2957906, JP 2017-511948.
  5. Yekkirala A.S., Roberson D.P., Bean B.P., Woolf C.J.: Breaking barriers to novel analgesic drug development. Nat. Rev. Drug Discovery 2017, 16, 545-564.
  6. Fryer A.D., Christopoulos A., Nathanson N.M.: Muscarinic Receptors. Handbook of Experimental Pharmacology, Springer 2012, ISBN 978-3-642-23273-2.
  7. del Puerto A., Wandosell F., Garrido J.J.: Neuronal and glial purinergic receptors functions in neuron development and brain disease. Front. Cell. Neurosci. 2013, 7,197.