Pirepemat

Last updated

Pirepemat
Pirepemat.svg
Clinical data
Other namesIRL-752; IRL752
Pharmacokinetic data
Elimination half-life 3.7–5.2 hours [1]
Identifiers
  • (3S)-3-(2,3-difluorophenyl)-3-methoxypyrrolidine
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
ChEMBL
Chemical and physical data
Formula C11H13F2NO
Molar mass 213.228 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

Pirepemat (INN Tooltip 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]

Contents

Pharmacology

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

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 INN Tooltip 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

Related Research Articles

<span class="mw-page-title-main">Tricyclic antidepressant</span> Class of medications

Tricyclic antidepressants (TCAs) are a class of medications that are used primarily as antidepressants. TCAs were discovered in the early 1950s and were marketed later in the decade. They are named after their chemical structure, which contains three rings of atoms. Tetracyclic antidepressants (TeCAs), which contain four rings of atoms, are a closely related group of antidepressant compounds.

<span class="mw-page-title-main">Chlorphenamine</span> Antihistamine used to treat allergies

Chlorphenamine (CP, CPM), also known as chlorpheniramine, is an antihistamine used to treat the symptoms of allergic conditions such as allergic rhinitis (hay fever). It is taken orally (by mouth). The medication takes effect within two hours and lasts for about 4–6 hours. It is a first-generation antihistamine and works by blocking the histamine H1 receptor.

<span class="mw-page-title-main">3,4-Methylenedioxyamphetamine</span> Empathogen-entactogen, psychostimulant, and psychedelic drug of the amphetamine family

3,4-Methylenedioxyamphetamine (MDA), sometimes referred to as “sass,” is an empathogen-entactogen, stimulant, and psychedelic drug of the amphetamine family that is encountered mainly as a recreational drug. In its pharmacology, MDA is a serotonin–norepinephrine–dopamine releasing agent (SNDRA). In most countries, the drug is a controlled substance and its possession and sale are illegal.

<span class="mw-page-title-main">Amoxapine</span> Tricyclic antidepressant medication

Amoxapine, sold under the brand name Asendin among others, is a tricyclic antidepressant (TCA). It is the N-demethylated metabolite of loxapine. Amoxapine first received marketing approval in the United States in 1980, approximately 10 to 20 years after most of the other TCAs were introduced in the United States.

<span class="mw-page-title-main">Phenylpiracetam</span> Chemical compound

Phenylpiracetam, also known as fonturacetam and sold under the brand names Phenotropil, Actitropil, and Carphedon among others, is a stimulant and nootropic medication used in Russia and certain other Eastern European countries in the treatment of cerebrovascular deficiency, depression, apathy, and attention, and memory problems, among other indications. It is also used in Russian cosmonauts to improve physical, mental, and cognitive abilities. The drug is taken by mouth.

<span class="mw-page-title-main">Lisuride</span> Chemical compound

Lisuride, sold under the brand name Dopergin among others, is a monoaminergic medication of the ergoline class which is used in the treatment of Parkinson's disease, migraine, and high prolactin levels. It is taken by mouth.

<span class="mw-page-title-main">Nicergoline</span> Chemical compound

Nicergoline, sold under the brand name Sermion among others, is an ergot derivative used to treat senile dementia and other disorders with vascular origins. Internationally it has been used for frontotemporal dementia as well as early onset in Lewy body dementia and Parkinson's dementia. It decreases vascular resistance and increases arterial blood flow in the brain, improving the utilization of oxygen and glucose by brain cells. It has similar vasoactive properties in other areas of the body, particularly the lungs. Unlike many other ergolines, such as ergotamine, nicergoline is not associated with cardiac fibrosis.

<span class="mw-page-title-main">Etoperidone</span> Chemical compound

Etoperidone, associated with several brand names, is an atypical antidepressant which was developed in the 1970s and either is no longer marketed or was never marketed. It is a phenylpiperazine related to trazodone and nefazodone in chemical structure and is a serotonin antagonist and reuptake inhibitor (SARI) similarly to them.

<span class="mw-page-title-main">Mesulergine</span> Chemical compound

Mesulergine (INNTooltip International Nonproprietary Name) (developmental code name CU-32085) is a drug of the ergoline group which was never marketed. It acts on serotonin and dopamine receptors. Specifically, it is an agonist of dopamine D2-like receptors and serotonin 5-HT6 receptors and an antagonist of serotonin 5-HT2A, 5-HT2B, 5-HT2C, and 5-HT7 receptors.. It also has affinity for the 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1F, and 5-HT5A receptors. The compound had entered clinical trials for the treatment of Parkinson's disease; however, further development was halted due to adverse histological abnormalities in rats. It was also investigated for the treatment of hyperprolactinemia (high prolactin levels).

<span class="mw-page-title-main">Benzofuranylpropylaminopentane</span> Chemical compound

(–)-Benzofuranylpropylaminopentane is an experimental drug related to selegiline which acts as a monoaminergic activity enhancer (MAE). It is orally active in animals.

<span class="mw-page-title-main">Nisoxetine</span> Chemical compound

Nisoxetine, originally synthesized in the Lilly research laboratories during the early 1970s, is a potent and selective inhibitor for the reuptake of norepinephrine (noradrenaline) into synapses. It currently has no clinical applications in humans, although it was originally researched as an antidepressant. Nisoxetine is now widely used in scientific research as a standard selective norepinephrine reuptake inhibitor. It has been used to research obesity and energy balance, and exerts some local analgesia effects.

<span class="mw-page-title-main">Medifoxamine</span> Withdrawn atypical antidepressant drug

Medifoxamine, previously sold under the brand names Clédial and Gerdaxyl, is an atypical antidepressant with additional anxiolytic properties acting via dopaminergic and serotonergic mechanisms which was formerly marketed in France and Spain, as well as Morocco. The drug was first introduced in France sometime around 1990. It was withdrawn from the market in 1999 (Morocco) and 2000 (France) following incidences of hepatotoxicity.

<span class="mw-page-title-main">Nemonapride</span> Antipsychotic medication

Nemonapride, also previously known as emonapride and sold under the brand name Emilace, is an atypical antipsychotic which is used in the treatment of schizophrenia. It is taken by mouth.

<span class="mw-page-title-main">Oxaprotiline</span> Chemical compound

Oxaprotiline, also known as hydroxymaprotiline, is a norepinephrine reuptake inhibitor belonging to the tetracyclic antidepressant (TeCA) family and is related to maprotiline. Though investigated as an antidepressant, it was never marketed.

<span class="mw-page-title-main">Pimavanserin</span> Atypical antipsychotic medication

Pimavanserin, sold under the brand name Nuplazid, is an atypical antipsychotic which is approved for the treatment of Parkinson's disease psychosis. Unlike other antipsychotics, pimavanserin is not a dopamine receptor antagonist, but rather is a selective inverse agonist of the serotonin 5-HT2A receptor.

<span class="mw-page-title-main">Serotonin antagonist and reuptake inhibitor</span> Class of drug

Serotonin antagonist and reuptake inhibitors (SARIs) are a class of drugs used mainly as antidepressants, but also as anxiolytics and hypnotics. They act by antagonizing serotonin receptors such as 5-HT2A and inhibiting the reuptake of serotonin, norepinephrine, and/or dopamine. Additionally, most also antagonize α1-adrenergic receptors. The majority of the currently marketed SARIs belong to the phenylpiperazine class of compounds.

<span class="mw-page-title-main">Pardoprunox</span> Antiparkinsonian compound researched for the treatment of depression and anxiety disorders

Pardoprunox (INN) is an antiparkinsonian drug developed by Solvay for the treatment of Parkinson's disease that reached phase III clinical trials before being discontinued. It was also being investigated for the treatment of depression and anxiety but these indications appear to have been abandoned as well.

<span class="mw-page-title-main">Clorotepine</span> Antipsychotic medication

Clorotepine, also known as octoclothepin or octoclothepine, is an antipsychotic of the tricyclic group which was derived from perathiepin in 1965 and marketed in the Czech Republic by Spofa in or around 1971 for the treatment of schizophrenic psychosis.

<span class="mw-page-title-main">Amesergide</span> Chemical compound

Amesergide is a serotonin receptor antagonist of the ergoline and lysergamide families related to methysergide which was under development by Eli Lilly and Company for the treatment of a variety of conditions including depression, anxiety, schizophrenia, male sexual dysfunction, migraine, and thrombosis but was never marketed. It reached phase II clinical trials for the treatment of depression, erectile dysfunction, and premature ejaculation prior to the discontinuation of its development.

<span class="mw-page-title-main">Mesdopetam</span> Chemical compound

Mesdopetam (INNTooltip International Nonproprietary Name; developmental code names IRL-790, IPN60170) is a dopamine D2 and D3 receptor antagonist with preference for the D3 receptor which is under development for the treatment of Parkinson's disease, drug-induced dyskinesia, and psychotic disorders. It has been described by its developers as having "psychomotor stabilizing" properties.

References

  1. 1 2 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. 1 2 3 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. 1 2 3 4 5 6 7 8 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. hdl: 10454/17970 . PMID   32605972.
  6. 1 2 3 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. 1 2 "Proposed INN: List 123 International Nonproprietary Names for Pharmaceutical Substances (INN)" (PDF). WHO Drug Information. 34 (2). 2020.
  8. 1 2 3 4 "Pirepemat". Synapse. 13 September 2024. Retrieved 27 September 2024.
  9. 1 2 3 4 5 6 7 8 9 "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.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.