Pridopidine

Pridopidine (formerly Huntexil, ACR16, also ASP2314) is an orally bioavailable small molecule investigational drug candidate. It is a highly selective Sigma-1 Receptor (S1R) agonist.[1][2] The S1R regulates key cellular processes relevant to neurodegenerative diseases, such as calcium homeostasis, cytoskeleton dynamics, restoring mitochondrial health and neurotrophic factor release. S1R is implicated in cellular differentiation, neuroplasticity, neuroprotection, and cognitive functioning of the brain.

Pridopidine
Names
IUPAC name
4-(3-(Methylsulfonyl)phenyl)-1-propylpiperidine
Identifiers
CAS Number
3D model (JSmol)
ChemSpider
ECHA InfoCard 100.240.998
KEGG
PubChem CID
UNII
Properties
Chemical formula
C15H23NO2S
Molar mass 281.41 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references

Pridopidine positively influences S1R regulated pathways across neurodegenerative and neurodevelopmental indications, including protection against axonal and neuronal injury, restoring spine impairments, enhancing BDNF secretion and restoring mitochondrial function.

Priodopine was previously thought to be a D2R antagonist but this was discovered to be incorrect.[3]

Pridopidine is in late-stage development by Prilenia Therapeutics. Previously it was owned by Teva Pharmaceutical Industries who acquired the rights to the product from its original developer NeuroSearch in 2012.

Pridopidine is the first drug to show statistically significant effect on maintenance of functional capacity in HD,[4] as measured by Total Functional Capacity (TFC). This effect was most prominent in early HD patients.[5]

While at low doses, Pridopidine affects S1R, at higher doses it interacts with other targets including dopamine D3, adrenergic α2C and serotoninergic 5-HT1A, which are established therapeutic targets for Parkinson's Disease Levodopa Induced Dyskinesia (PD-LID). This is the likely mechanism for the clear effect seen in the “gold standard” non-human primate model for PD-LID – the MPTP-Lesioned Macaques.[6] This model is considered highly translatable to success in phase 2 clinical trials.

Pridopidine is currently in phase 2 clinical for PD-LID,[7] and was recently chosen[8][9] to participate in a novel platform trial for ALS by the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital.

References

  1. Johnston, Tom H.; Geva, Michal; Steiner, Lilach; Orbach, Aric; Papapetropoulos, Spyros; Savola, Juha-Matti; Reynolds, Ian J.; Ravenscroft, Paula; Hill, Michael (May 2019). "Pridopidine, a clinic-ready compound, reduces 3,4-dihydroxyphenylalanine-induced dyskinesia in Parkinsonian macaques". Movement Disorders. 34 (5): 708–716. doi:10.1002/mds.27565. ISSN 1531-8257. PMID 30575996.
  2. Sahlholm, Kristoffer; Sijbesma, Jurgen W. A.; Maas, Bram; Kwizera, Chantal; Marcellino, Daniel; Ramakrishnan, Nisha K.; Dierckx, Rudi A. J. O.; Elsinga, Philip H.; van Waarde, Aren (September 2015). "Pridopidine selectively occupies sigma-1 rather than dopamine D2 receptors at behaviorally active doses". Psychopharmacology. 232 (18): 3443–3453. doi:10.1007/s00213-015-3997-8. ISSN 1432-2072. PMC 4537502. PMID 26159455.
  3. Sahlholm, Kristoffer; Sijbesma, Jurgen W. A.; Maas, Bram; Kwizera, Chantal; Marcellino, Daniel; Ramakrishnan, Nisha K.; Dierckx, Rudi A. J. O.; Elsinga, Philip H.; van Waarde, Aren (September 2015). "Pridopidine selectively occupies sigma-1 rather than dopamine D2 receptors at behaviorally active doses". Psychopharmacology. 232 (18): 3443–3453. doi:10.1007/s00213-015-3997-8. ISSN 1432-2072. PMC 4537502. PMID 26159455.
  4. "Huntington's Patients May See Delay in Fuctional Decline with Pridopidine". Huntington's Disease News. 2017-04-20. Retrieved 2019-09-21.
  5. "Trial finds Teva drug could slow Huntington's disease". en.globes.co.il (in Hebrew). 2016-09-19. Retrieved 2019-09-21.
  6. Johnston, Tom H.; Geva, Michal; Steiner, Lilach; Orbach, Aric; Papapetropoulos, Spyros; Savola, Juha-Matti; Reynolds, Ian J.; Ravenscroft, Paula; Hill, Michael (May 2019). "Pridopidine, a clinic-ready compound, reduces 3,4-dihydroxyphenylalanine-induced dyskinesia in Parkinsonian macaques". Movement Disorders. 34 (5): 708–716. doi:10.1002/mds.27565. ISSN 1531-8257. PMID 30575996.
  7. "A Study to Assess the Safety and Effectiveness of Pridopidine Compared to Placebo in the Treatment of Levodopa-Induced Dyskinesia in Patients With Parkinson's Disease - Full Text View - ClinicalTrials.gov". clinicaltrials.gov. Retrieved 2019-09-21.
  8. "Sean M. Healey & AMG Center for ALS at Mass General launches first ALS Platform Trial with 5 promising drugs". Massachusetts General Hospital. Retrieved 2019-09-21.
  9. "Prilenia's Pridopidine Chosen to Participate in the First ALS Platform Trial". www.businesswire.com. 2019-09-18. Retrieved 2019-09-21.
  10. Seeman P, Tokita K, Matsumoto M, Matsuo A, Sasamata M, Miyata K (October 2009). "The dopaminergic stabilizer ASP2314/ACR16 selectively interacts with D2(High) receptors". Synapse. 63 (10): 930–4. doi:10.1002/syn.20663. PMID 19588469.
  11. Rung JP, Rung E, Helgeson L, et al. (June 2008). "Effects of (-)-OSU6162 and ACR16 on motor activity in rats, indicating a unique mechanism of dopaminergic stabilization". Journal of Neural Transmission. 115 (6): 899–908. doi:10.1007/s00702-008-0038-3. PMID 18351286.
  12. "NeuroSearch A/S announces the results of additional assessment and analysis of data from the Phase III MermaiHD study with Huntexil® in Huntington's disease" (Press release). NeuroSearch. 28 April 2010. Retrieved 2010-04-28.
  13. Ponten, H.; Kullingsjö, J.; Lagerkvist, S.; Martin, P.; Pettersson, F.; Sonesson, C.; Waters, S.; Waters, N. (2003-11-19) [2000-12-22]. "In vivo pharmacology of the dopaminergic stabilizer pridopidine". European Journal of Pharmacology. 644 (1–3): 88–95. doi:10.1016/j.ejphar.2010.07.023. PMID 20667452.
  14. Natesan S, Svensson KA, Reckless GE, et al. (August 2006). "The dopamine stabilizers (S)-(-)-(3-methanesulfonyl-phenyl)-1-propyl-piperidine [(-)-OSU6162] and 4-(3-methanesulfonylphenyl)-1-propyl-piperidine (ACR16) show high in vivo D2 receptor occupancy, antipsychotic-like efficacy, and low potential for motor side effects in the rat". The Journal of Pharmacology and Experimental Therapeutics. 318 (2): 810–8. doi:10.1124/jpet.106.102905. PMID 16648369.
  15. Rung JP, Carlsson A, Markinhuhta KR, Carlsson ML (June 2005). "The dopaminergic stabilizers (-)-OSU6162 and ACR16 reverse (+)-MK-801-induced social withdrawal in rats". Progress in Neuro-psychopharmacology & Biological Psychiatry. 29 (5): 833–9. doi:10.1016/j.pnpbp.2005.03.003. PMID 15913873.
  16. Nilsson M, Carlsson A, Markinhuhta KR, et al. (July 2004). "The dopaminergic stabiliser ACR16 counteracts the behavioural primitivization induced by the NMDA receptor antagonist MK-801 in mice: implications for cognition". Progress in Neuro-psychopharmacology & Biological Psychiatry. 28 (4): 677–85. doi:10.1016/j.pnpbp.2004.05.004. PMID 15276693.
  17. Dyhring T, Nielsen EØ, Sonesson C, et al. (February 2010). "The dopaminergic stabilizers pridopidine (ACR16) and (-)-OSU6162 display dopamine D(2) receptor antagonism and fast receptor dissociation properties". European Journal of Pharmacology. 628 (1–3): 19–26. doi:10.1016/j.ejphar.2009.11.025. PMID 19919834.
  18. Pettersson, F; Pontén, H; Waters N; Waters S; Sonesson C (March 2010). "Synthesis and Evaluation of a Set of 4-Phenylpiperidines and 4-Phenylpiperazines as D2 Receptor Ligands and the Discovery of the Dopaminergic Stabilizer 4-[3-(methylsulfonyl)phenyl]-1-propylpiperidine (Pridopidine; ACR16)". Journal of Medicinal Chemistry. 53 (6): 2510–2520. doi:10.1021/jm901689v. PMID 20155917.
  19. Tadori Y, Forbes RA, McQuade RD, Kikuchi T (November 2008). "Characterization of aripiprazole partial agonist activity at human dopamine D3 receptors". European Journal of Pharmacology. 597 (1–3): 27–33. doi:10.1016/j.ejphar.2008.09.008. PMID 18831971.
  20. Pettersson F, Waters N, Waters ES, Carlsson A, Sonesson C (November 7, 2002). The development of a new class of dopamine stabilizers. Society for Neuroscience Annual Conference. Orlando, FL.
  21. Tedroff, J.; Krogh, P. Lindskov; Buusman, A.; Rembratt, Å. (2010). "Poster 20: Pridopidine (ACR16) in Huntington's Disease: An Update on the MermaiHD and HART Studies". Neurotherapeutics. 7: 144–145. doi:10.1016/j.nurt.2009.10.004.
  22. "NeuroSearch announces results from an open-label safety extension to the Phase III MermaiHD study of Huntexil® in patients with Huntington's disease" (Press release). NeuroSearch. 15 September 2010. Retrieved 2010-09-15.
  23. "The HART study with Huntexil® shows significant effect on total motor function in patients with Huntington's disease although it did not meet the primary endpoint after 12 weeks of treatment" (Press release). NeuroSearch. 14 October 2010. Retrieved 2010-10-14.
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