Neuroactive steroids - use dependent inhibitors of NMDA receptors

Transcription

1 Neuroactive steroids - use dependent inhibitors of NMDA receptors Vales K., Chodounska H., Vyklicky L., et al. with the financial support of

2 Fields of interest Treatment of neuropsychiatric disorders related to imbalance of glutamatergic and GABAergic neurotransmitter systems. Neuroprotection Depression Market size ~ 50 B $ Other: neurodegeneration, psychosis, neuropathic pain, epilepsy, addiction Page 2

3 Current therapy challanges Current therapeutic strategie suffer either low effectivity or serve adverse effects Marketed antidepressants are low effective and usually Regulate amount of serotonin, dopamine and norepinephrine Adverse effects and long onset of action (4-8 weeks) is significant complication Current Neuroprotective therapy Drugs could be ineffective in singificant part patient popupation and serve adverse effects were observed. Neuropathic pain therapy Unsatisfactory efficacy and safety profiles of pharmacological treatments (only one in four patients achieves over 50% pain relief ) Unmet medical need and significant market potential for novel small-molecule drugs with excellent safety profile has been identified. Page 3

4 Novel promising compounds Use dependent inhibitors of NMDA receptors Derivatives of pregnanolone Page 4

5 Proof of concept Neuroprotection The designed neuroactive steroids are capable to: reverse hypoxic/ischemic damage in perinatal insult model via modulation of GABA A and NMDA receptor (Kleteckova et al., 2014) reduce an excitotoxic damage of brain tissue and subsequent behavioral impairment in rats. (Rambousek et al., 2011) Page 5

6 Proof of concept Depression The designed neuroactive steroids suggest antidepressant- and anxiolitic-like properties and together demonstrate minimal side effects (Holubova et al., 2014). Neurosteroids as potent NMDA receptor inhibitor and GABA A receptor agonists might be promising therapeutic agents in depressive disorders (Zorumski et al., 2013) Page 6

7 Proof of concept The animal models of another psychiatric disorders: The designed neuroactive steroids are capable to: improve cognitive deficit in an animal model of schizophrenia (Vales et al., 2012) reduce neuropathic pain in animal models Page 7

8 Results summary Neuroactive steroids: showed use-dependent inhibiton to NMDA receptor (in vitro) penetrate blood brain barrier and rapidly enter the brain (t max = 60 min) do not show adverse effects typical for classical NMDA channel blockers low toxicity in vitro and in vivo has been observed show neuroprotective effects in animal models: NMDA lesion of hippocampus Focal cerebral ischemia in immature rats show antidepressant like effect in animal models: Forced swimming Social defeat Page 8

9 Development and IP status Chemistry ~240 original compounds prepared and tested (by now) improvement of solubility and bioavailability is under development lead structure optimization Biology (early preclinical stage) IP Pharmacokinetic properties and toxicity screening In vitro testing (NMDA and GABA A receptors) In vivo testing in animal models of CNS diseases 3 relevant patent families (EP and US patents) with the most recent priority date in Further application is under preparation. Page 9

10 Acknowledgement and contacts This is a project of Center for Development of Original Drugs with the financial support of Jirina Borovska Ales Stuchlik Lukas Rambousek Ladislav Vyklicky Vojtech Vyklicky Grigoriy Tsenov Lenka Kleteckova Hana Chodounska Vojtech Kapras Eva Kudová Karel Vales tel.: Jaromir Zahradka zahradka@iocb-tto.cz tel.: