Wikipedia

Pirepemat

Pirepemat (INNTooltip International Nonproprietary Name; developmental code name IRL752 or IRL-752) is a drug which is under development for the prevention of falls in people with Parkinson's disease and Parkinson's disease dementia.[2][3][4][5][1][6] It has been referred to as a "nootrope" (i.e., nootropic or cognitive enhancer).[7]

Pirepemat
Clinical data
Other namesIRL-752; IRL752
Pharmacokinetic data
Elimination half-life3.7–5.2 hours[1]
Identifiers
  • (3S)-3-(2,3-difluorophenyl)-3-methoxypyrrolidine
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
ChEMBL
Chemical and physical data
FormulaC11H13F2NO
Molar mass213.228 g·mol−1
3D model (JSmol)
  • CO[C@@]1(CCNC1)C2=C(C(=CC=C2)F)F
  • InChI=1S/C11H13F2NO/c1-15-11(5-6-14-7-11)8-3-2-4-9(12)10(8)13/h2-4,14H,5-7H2,1H3/t11-/m1/s1
  • Key:LJNFYMMXCXGFCP-LLVKDONJSA-N

Pharmacology

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Pirepemat shows affinity for several neurotransmitter receptors and transporters.[8][9][5] These include the serotonin 5-HT7 receptor (Ki = 980 nM), the sigma σ1 receptor (Ki = 1,200 nM), the serotonin transporter (SERT) (Ki = 2,500 nM), the α2C-adrenergic receptor (Ki = 3,800 nM), the α2A-adrenergic receptor (Ki = 6,500 nM), the serotonin 5-HT2C receptor (Ki = 6,600 nM), the serotonin 5-HT2A receptor (Ki = 8,100 nM), and the norepinephrine transporter (NET) (Ki = 8,100 nM).[8][9][5] It also shows affinity for the rat κ-opioid receptor (KOR) (Ki = 6,500 nM) and has weak affinity for the α1-adrenergic receptor (Ki = 21,000 nM).[5] The drug was an antagonist or inhibitor at all assessed targets (which included some but not all of the preceding sites).[8][9][5]

Pirepemat has been described as a "cortical enhancer" and has been reported to region-specifically increase norepinephrine, dopamine, and acetylcholine levels in the cerebral cortex.[2][5] Serotonin 5-HT7 receptor antagonism and α2-adrenergic receptor antagonism were hypothesized to underlie these effects.[9][5] In animals, pirepemat has been found to reverse hypoactivity induced by the dopamine depleting agent tetrabenazine whilst not increasing basal locomotor activity and not affecting or minimally influencing dextroamphetamine- and dizocilpine-induced locomotor hyperactivity.[6][5]

Clinical trials

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The drug was reported to improve motivation and reduce apathy in people with Parkinson's disease in a phase 2a clinical trial.[10][2][6]

As of September 2024, pirepemat is in phase 2 clinical trials for Parkinson's disease.[9][8] A phase 3 trial is being planned.[9] The drug was also under development for the treatment of "behavioral disorders" and attention deficit hyperactivity disorder (ADHD).[9] However, no recent development for the former indication has been reported and development for ADHD was discontinued.[9] In August 2020, pirepemat received an INNTooltip International Nonproprietary Name with a novel suffix reflecting its reputedly new and unique mechanism of action.[11][7] Pirepemat is under development by Integrative Research Laboratories (IRLAB).[9]

See also

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References

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  1. ^ a b Rein-Hedin E, Sjöberg F, Waters S, Sonesson C, Waters N, Huss F, et al. (December 2021). "First-in-Human Study to Assess the Safety, Tolerability, and Pharmacokinetics of Pirepemat, a Cortical Enhancer, in Healthy Volunteers". Clin Pharmacol Drug Dev. 10 (12): 1485–1494. doi:10.1002/cpdd.959. PMID 34118179.
  2. ^ a b c Maher S, Donlon E, Mullane G, Walsh R, Lynch T, Fearon C (April 2024). "Treatment of Apathy in Parkinson's Disease and Implications for Underlying Pathophysiology". J Clin Med. 13 (8): 2216. doi:10.3390/jcm13082216. PMC 11051068. PMID 38673489.
  3. ^ Phillips O, Ghosh D, Fernandez HH (May 2023). "Parkinson Disease Dementia Management: an Update of Current Evidence and Future Directions". Current Treatment Options in Neurology. 25 (5). Springer Science and Business Media LLC: 93–119. doi:10.1007/s11940-023-00749-4. ISSN 1092-8480.
  4. ^ Wolff A, Schumacher NU, Pürner D, Machetanz G, Demleitner AF, Feneberg E, et al. (June 2023). "Parkinson's disease therapy: what lies ahead?". J Neural Transm (Vienna). 130 (6): 793–820. doi:10.1007/s00702-023-02641-6. PMC 10199869. PMID 37147404.
  5. ^ a b c d e f g h Hjorth S, Waters S, Waters N, Tedroff J, Svensson P, Fagerberg A, et al. (September 2020). "(3S)-3-(2,3-difluorophenyl)-3-methoxypyrrolidine (IRL752) -a Novel Cortical-Preferring Catecholamine Transmission- and Cognition-Promoting Agent". J Pharmacol Exp Ther. 374 (3): 404–419. doi:10.1124/jpet.120.000037. PMID 32605972.
  6. ^ a b c Svenningsson P, Odin P, Dizdar N, Johansson A, Grigoriou S, Tsitsi P, et al. (June 2020). "A Phase 2a Trial Investigating the Safety and Tolerability of the Novel Cortical Enhancer IRL752 in Parkinson's Disease Dementia". Mov Disord. 35 (6): 1046–1054. doi:10.1002/mds.28020. PMID 32198802.
  7. ^ a b "Proposed INN: List 123 International Nonproprietary Names for Pharmaceutical Substances (INN)" (PDF). WHO Drug Information. 34 (2). 2020.
  8. ^ a b c d "Pirepemat". Synapse. 13 September 2024. Retrieved 27 September 2024.
  9. ^ a b c d e f g h i "Pirepemat (IRL-752) - Integrative Research Laboratories". AdisInsight. Springer Nature Switzerland AG. 26 September 2024. Retrieved 26 September 2024.
  10. ^ Theleritis C, Siarkos K, Politis A, Smyrnis N, Papageorgiou C, Politis AM (July 2023). "A Systematic Review of Pharmacological Interventions for Apathy in Aging Neurocognitive Disorders". Brain Sci. 13 (7): 1061. doi:10.3390/brainsci13071061. PMC 10377475. PMID 37508993.
  11. ^ IRLAB Therapeutics AB (3 August 2020). "IRLAB's IRL752 is proposed pirepemat as a unique INN by WHO". PR Newswire. Retrieved 27 September 2024.
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