Pirepemat Explained

Width:100px
Elimination Half-Life:3.7–5.2 hours[1]
Cas Number:1227638-29-0
Pubchem:135381565
Drugbank:DB19165
Chemspiderid:115009507
Unii:JS88RK5NOI
Chembl:5095193
Synonyms:IRL-752; IRL752
Iupac Name:(3S)-3-(2,3-difluorophenyl)-3-methoxypyrrolidine
C:11
H:13
F:2
N:1
O:1
Smiles:CO[C@@]1(CCNC1)C2=C(C(=CC=C2)F)F
Stdinchi: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
Stdinchikey:LJNFYMMXCXGFCP-LLVKDONJSA-N

Pirepemat (; 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] [6] It has been referred to as a "nootrope" (i.e., nootropic or cognitive enhancer).[7]

Pharmacology

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

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. Serotonin 5-HT7 receptor antagonism and α2-adrenergic receptor antagonism were hypothesized to underlie these effects. 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.

Clinical trials

The drug was reported to improve motivation and reduce apathy in people with Parkinson's disease in a phase 2a clinical trial.[9]

As of September 2024, pirepemat is in phase 2 clinical trials for Parkinson's disease.[10] A phase 3 trial is being planned. The drug was also under development for the treatment of "behavioral disorders" and attention deficit hyperactivity disorder (ADHD). However, no recent development for the former indication has been reported and development for ADHD was discontinued. In August 2020, pirepemat received an with a novel suffix reflecting its reputedly new and unique mechanism of action.[11] Pirepemat is under development by Integrative Research Laboratories (IRLAB).

See also

External links

Notes and References

  1. Rein-Hedin E, Sjöberg F, Waters S, Sonesson C, Waters N, Huss F, Tedroff J . 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 . December 2021 . 34118179 . 10.1002/cpdd.959 .
  2. Maher S, Donlon E, Mullane G, Walsh R, Lynch T, Fearon C . Treatment of Apathy in Parkinson's Disease and Implications for Underlying Pathophysiology . J Clin Med . 13 . 8 . April 2024 . 2216 . 38673489 . 11051068 . 10.3390/jcm13082216 . free .
  3. Phillips O, Ghosh D, Fernandez HH . Parkinson Disease Dementia Management: an Update of Current Evidence and Future Directions . Current Treatment Options in Neurology . Springer Science and Business Media LLC . 25 . 5 . May 2023 . 1092-8480 . 10.1007/s11940-023-00749-4 . 93–119.
  4. Wolff A, Schumacher NU, Pürner D, Machetanz G, Demleitner AF, Feneberg E, Hagemeier M, Lingor P . Parkinson's disease therapy: what lies ahead? . J Neural Transm (Vienna) . 130 . 6 . 793–820 . June 2023 . 37147404 . 10199869 . 10.1007/s00702-023-02641-6 .
  5. Hjorth S, Waters S, Waters N, Tedroff J, Svensson P, Fagerberg A, Edling M, Svanberg B, Ljung E, Gunnergren J, McLean SL, Grayson B, Idris NF, Neill JC, Sonesson C . (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 . September 2020 . 32605972 . 10.1124/jpet.120.000037 . 10454/17970 . free .
  6. Svenningsson P, Odin P, Dizdar N, Johansson A, Grigoriou S, Tsitsi P, Wictorin K, Bergquist F, Nyholm D, Rinne J, Hansson F, Sonesson C, Tedroff J . 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 . June 2020 . 32198802 . 10.1002/mds.28020 .
  7. WHO Drug Information . 34 . 2 . 2020 . Proposed INN: List 123 International Nonproprietary Names for Pharmaceutical Substances (INN).
  8. Web site: Pirepemat . Synapse . 13 September 2024 . 27 September 2024.
  9. Theleritis C, Siarkos K, Politis A, Smyrnis N, Papageorgiou C, Politis AM . A Systematic Review of Pharmacological Interventions for Apathy in Aging Neurocognitive Disorders . Brain Sci . 13 . 7 . July 2023 . 1061 . 37508993 . 10377475 . 10.3390/brainsci13071061 . free .
  10. Web site: Pirepemat (IRL-752) - Integrative Research Laboratories . AdisInsight . Springer Nature Switzerland AG . 26 September 2024 . 26 September 2024.
  11. Web site: IRLAB Therapeutics AB . IRLAB's IRL752 is proposed pirepemat as a unique INN by WHO . PR Newswire . 3 August 2020 . 27 September 2024.

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