TIK-301

Last updated
TIK-301
LY-156735.png
Clinical data
Other namesBeta-methyl-6-chloromelatonin; LY-156735; PD-6735
Routes of
administration 		Oral
Legal status
Legal status
  • Investigational
Pharmacokinetic data
Elimination half-life 1 hour
Identifiers
  • N-[(2R)-(6-Chloro-5-methoxy-1H-indol-3-yl)propyl]acetamide
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C14H17ClN2O2
Molar mass 280.75 g·mol−1
3D model (JSmol)
  • C[C@@H](CNC(=O)C)c1c[nH]c2c1cc(c(c2)Cl)OC
  • InChI=1S/C14H17ClN2O2/c1-8(6-16-9(2)18)11-7-17-13-5-12(15)14(19-3)4-10(11)13/h4-5,7-8,17H,6H2,1-3H3,(H,16,18)/t8-/m0/s1 X mark.svgN
  • Key:RKHCTAKUYDTFHE-QMMMGPOBSA-N X mark.svgN
 X mark.svgNYes check.svgY  (what is this?)    (verify)

TIK-301 (LY-156735) is an agonist for the melatonin receptors MT1 and MT2 that is under development for the treatment of insomnia and other sleep disorders. [1] Its agonist action on MT1 and MT2 receptors in the suprachiasmatic nucleus in the brain enables its action as a chronobiotic. It is in the same class of melatonin receptor agonists as ramelteon and tasimelteon.

Contents

History and development

TIK-301 was first developed at Eli Lilly and Co in Indianapolis, IN as LY-156735. In 2002, it was licensed by Phase 2 Discovery for further commercialization and worldwide development as PD-6735. [2] [3] In July 2007, the open Investigational New Drug (IND) was transferred to Tikvah Therapeutics Inc. in Atlanta, GA by Phase II Discovery, where it was renamed to TIK-301. Currently, clinical trials are ongoing there. [4] [5] [6] Because it has been traded and sublicensed by multiple companies, it can referred to by all three names. Mostly recently and commonly, it is referred to as TIK-301.

TIK-301 was in phase II clinical trials in 2002. [2] In 2004, TIK-301 was designated an orphan drug by the FDA. [2] [7]

Pharmacodynamics

TIK-301 is a high affinity nonselective MT1/MT2 agonist. [8] Studies show that it is more potent and more effective than melatonin. Its affinity for MT1 is similar to that of melatonin (pKi =10.38, Ki=81pM) and its affinity for MT2 is slightly higher (pKi=10.38, Ki= 42pM). [2] [8] [9] [10] [11] This enantiomer had higher affinity for the binding site compared to the racemic mixture. [2] The MT1/MT2 Ki ratio is 1.9. [12] This slight preference for MT2 receptor is common among melatonin derivatives with chlorine. [9] [12] TIK-301's action on MT1 and MT2 receptors contributes to its sleep-promoting effects because melatonin's effects at these same receptors is linked with maintenance of normal-sleep wake cycle. TIK-301 was shown to be effective at promoting sleep at various doses; there is a positive dose response relationship between dose and reduction in sleep latency. [13] The EC50 of TIK-301 is 0.0479nM, compared to 0.063nM for melatonin. [8] It also acts as an antagonist at serotonin receptors 5-HT2B and 5-HT2C. [9]

Pharmacokinetics

TIK-301 is administered orally. [14] Compared to melatonin, it has nine times greater bioavailability and six times greater area under the curve (AUC), which means the body retains more of an administered dose. [13] [14] TIK-301 was detected in blood plasma within 10 to 15 minutes of administration of a single oral dose and remains in a patient's system until 12 hours after the single dose. [13] Plasma concentrations increased rapidly and peaked at 1 hour after the dose, independent of dose size. [13] TIK-301's half-life is about 1 hour. [9] [13] This extended half-life may be partially due to the chlorine in its structure. [11] Elimination constants depended on dose, 20 mg dose had a different elimination constant from all other doses above 35 mg. [13]

Treatment

TIK-301 is intended to be a take-as-need drug for primary insomnia, circadian rhythm disorders, depression, as well as sleep disorders in blind individuals and can be used to alleviate neuroleptic-induced tardive dyskinesia in schizophrenia patients. [15] In a phase I clinical trial, TIK-301 was shown to be effective as a chronobiotic at a dose of 5 mg/L, but not in lower doses. [14] In a phase II trial for primary insomnia, patients experienced objective and subjective improvements in sleep latency at 20 mg (31% improvement), 50 mg (32%) and 100 mg (41%) doses. [16] The sleep latency improvement at the 100 mg dose is comparable to FDA approved zolpidem's effects. [16] Surprisingly, it showed no such effects in healthy patients when taken before bed. [17] In a test of phase shifted circadian cycle, TIK-301 showed efficacy in readjusting phase shifts in all physiological systems. [14] [18] While it has been shown to be effective in phase shifting circadian rhythm and reduced sleep latency, it has not been shown to help sleep maintenance, even at doses of 20 mg or 200 mg. [11]

In addition to a sleep aid, TIK-301 has been found useful in treating other disorders. Because of its affinity for serotonin receptors, it has potential to serve as a possible antidepressant drug, similar to agomelatine. [8] [9] [19] TIK-301 has also been considered for use in patients with mild cognitive impairment (MCI) because of sleep disorder prevalence. [15] TIK-301, as well as other melatonin agonists, has been reported to have potential in preventing or treating urinary incontinence, but have not been tested in humans for this purpose. [20] [21] It is also seen as a potential therapeutic agent for spinal cord injury (SCI); in low doses (10 mg/kg) it was seen to be benefit in rats after SCI, but in higher doses (100 mg/kg), it proved toxic. [22]

Side effects

There were no major and serious side effects in phase I trials, and mild side effects such as diarrhea, conjunctivitis and laryngitis were observed in few cases. [14] [16] Unlike benzodiazepines sleep medications, TIK-301's novel mode of action at melatonin receptors reduce many common side effects of sleep medications like dependency. In addition, TIK-301 had no latent, morning after psychomotor impairments. [16] A few patients reported cases of somnolence in clinical trials, which is consistent with the drug's soporific effects. [13]

Because of its receptor specific action, there are no associated changes in core body temperatures, heart rate or blood pressure as with other melatonin medications. [13] [15] [16] [17]

Related Research Articles

<span class="mw-page-title-main">Delayed sleep phase disorder</span> Chronic mismatch between a persons normal daily rhythm, compared to other people and societal norms

Delayed sleep phase disorder (DSPD), more often known as delayed sleep phase syndrome and also as delayed sleep–wake phase disorder, is the delaying of a person's circadian rhythm compared to those of societal norms. The disorder affects the timing of biological rhythms including sleep, peak period of alertness, core body temperature, and hormonal cycles.

Non-24-hour sleep–wake disorder is one of several chronic circadian rhythm sleep disorders (CRSDs). It is defined as a "chronic steady pattern comprising [...] daily delays in sleep onset and wake times in an individual living in a society". Symptoms result when the non-entrained (free-running) endogenous circadian rhythm drifts out of alignment with the light–dark cycle in nature. Although this sleep disorder is more common in blind people, affecting up to 70% of the totally blind, it can also affect sighted people. Non-24 may also be comorbid with bipolar disorder, depression, and traumatic brain injury. The American Academy of Sleep Medicine (AASM) has provided CRSD guidelines since 2007 with the latest update released in 2015.

<span class="mw-page-title-main">Eszopiclone</span> Hypnotic medication

Eszopiclone, sold under the brand name Lunesta among others, is a medication used in the treatment of insomnia. Evidence supports slight to moderate benefit up to six months. It is taken by mouth.

<span class="mw-page-title-main">Doxepin</span> Medication to treat depressive disorder, anxiety disorders, chronic hives, and trouble sleeping

Doxepin is a medication belonging to the tricyclic antidepressant (TCA) class of drugs used to treat major depressive disorder, anxiety disorders, chronic hives, and insomnia. For hives it is a less preferred alternative to antihistamines. It has a mild to moderate benefit for sleeping problems. It is used as a cream for itchiness due to atopic dermatitis or lichen simplex chronicus.

<span class="mw-page-title-main">Agomelatine</span> Atypical antidepressant classified primarily as a melatonin receptor agonist

Agomelatine, sold under the brand names Valdoxan and Thymanax, among others, is an atypical antidepressant most commonly used to treat major depressive disorder and generalized anxiety disorder. One review found that it is as effective as other antidepressants with similar discontinuation rates overall but fewer discontinuations due to side effects. Another review also found it was similarly effective to many other antidepressants.

<span class="mw-page-title-main">Ramelteon</span> Hypnotic medication

Ramelteon, sold under the brand name Rozerem among others, is a melatonin agonist medication which is used in the treatment of insomnia. It is indicated specifically for the treatment of insomnia characterized by difficulties with sleep onset. It reduces the time taken to fall asleep, but the degree of clinical benefit is small. The medication is approved for long-term use. Ramelteon is taken by mouth.

Melatonin receptors are G protein-coupled receptors (GPCR) which bind melatonin. Three types of melatonin receptors have been cloned. The MT1 (or Mel1A or MTNR1A) and MT2 (or Mel1B or MTNR1B) receptor subtypes are present in humans and other mammals, while an additional melatonin receptor subtype MT3 (or Mel1C or MTNR1C) has been identified in amphibia and birds. The receptors are crucial in the signal cascade of melatonin. In the field of chronobiology, melatonin has been found to be a key player in the synchrony of biological clocks. Melatonin secretion by the pineal gland has circadian rhythmicity regulated by the suprachiasmatic nucleus (SCN) found in the brain. The SCN functions as the timing regulator for melatonin; melatonin then follows a feedback loop to decrease SCN neuronal firing. The receptors MT1 and MT2 control this process. Melatonin receptors are found throughout the body in places such as the brain, the retina of the eye, the cardiovascular system, the liver and gallbladder, the colon, the skin, the kidneys, and many others. In 2019, X-ray crystal and cryo-EM structures of MT1 and MT2 were reported.

<i>N</i>-Acetylserotonin Chemical compound

N-Acetylserotonin (NAS), also known as normelatonin, is a naturally occurring chemical intermediate in the endogenous production of melatonin from serotonin. It also has biological activity in its own right, including acting as a melatonin receptor agonist, an agonist of the TrkB, and having antioxidant effects.

<span class="mw-page-title-main">Tasimelteon</span> Wakefulness medication

Tasimelteon, sold under the brand name Hetlioz, is a medication approved by the U.S. Food and Drug Administration (FDA) in January 2014, for the treatment of non-24-hour sleep–wake disorder. In June 2014, the European Medicines Agency (EMA) accepted an EU filing application for tasimelteon and in July 2015, the drug was approved in the European Union for the treatment of non-24-hour sleep-wake rhythm disorder in totally blind adults, but not in the case of non-24 in sighted people.

<span class="mw-page-title-main">Esmirtazapine</span> Drug formerly under development for treatment of menopause symptoms

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<span class="mw-page-title-main">Melatonin receptor agonist</span>

Melatonin receptor agonists are analogues of melatonin that bind to and activate the melatonin receptor. Agonists of the melatonin receptor have a number of therapeutic applications including treatment of sleep disorders and depression. The discovery and development of melatonin receptor agonists was motivated by the need for more potent analogues than melatonin, with better pharmacokinetics and longer half-lives. Melatonin receptor agonists were developed with the melatonin structure as a model.

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

Nelotanserin is a drug developed by Arena Pharmaceuticals which acts as an inverse agonist on the serotonin receptor subtype 5-HT2A and was under development for the treatment of insomnia. It was shown to be effective and well tolerated in clinical trials, but development was halted in December 2008 because the substance did not meet the trial's effectiveness endpoints. Research continues on newer analogues which may potentially be more successful.

<span class="mw-page-title-main">Suvorexant</span> Medication used to treat insomnia

Suvorexant, sold under the brand name Belsomra, is an orexin antagonist medication which is used in the treatment of insomnia. It is indicated specifically for the treatment of insomnia characterized by difficulties with sleep onset and/or maintenance in adults. Suvorexant helps with falling asleep faster, sleeping longer, being awake less in the middle of the night, and having better quality of sleep. Its effectiveness is modest, and is similar to that of other orexin antagonists, but is lower than that of benzodiazepines and Z-drugs. Suvorexant is taken by mouth.

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

Piromelatine (Neu-P11) is a multimodal sleep drug under development by Neurim Pharmaceuticals. It is an agonist at melatonin MT1/MT2 and serotonin 5-HT1A/5-HT1D receptors. Neurim is conducting a phase II randomized, placebo controlled trial of cognitive and sleep effects in Alzheimer's disease.

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

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<span class="mw-page-title-main">Daridorexant</span> Medication used to treat insomnia

Daridorexant, sold under the brand name Quviviq, is an orexin antagonist medication which is used for the treatment of insomnia. Daridorexant is taken by mouth.

<span class="mw-page-title-main">Melatonin as a medication and supplement</span> Supplement and medication used to treat sleep disorders

Melatonin is a dietary supplement and medication as well as naturally occurring hormone. As a hormone, melatonin is released by the pineal gland and is involved in sleep–wake cycles. As a supplement, it is often used for the attempted short-term treatment of disrupted sleep patterns, such as from jet lag or shift work, and is typically taken orally. Evidence of its benefit for this use, however, is not strong. A 2017 review found that sleep onset occurred six minutes faster with use, but found no change in total time asleep.

Gabriella Gobbi is an Italo-Canadian psychiatrist and neuroscientist whose research explores novel treatments for mental health disorders. Gobbi is a professor at McGill University's Department of Psychiatry and a Canada Research Chair in Therapeutics for Mental Health.

<span class="mw-page-title-main">Somnifacient</span> Class of medications that induce sleep

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References

  1. ↑ "PD-6735, LY-156735,118702-11-7,C14-H17-Cl-N2-O2,N-[2(R)-(6-C--药物合成数据库". Archived from the original on 2009-09-27.
  2. 1 2 3 4 5 Rivara S, Mor M, Bedini A, Spadoni G, Tarzia G (2008). "Melatonin receptor agonists: SAR and applications to the treatment of sleep-wake disorders". Current Topics in Medicinal Chemistry. 8 (11): 954–968. doi:10.2174/156802608784936719. PMID   18673165.
  3. ↑ Mody S, Hu Y, Ho MK, Wong YH (2011-08-12). Frontiers in CNS Drug Discovery. Bentham eBooks. p. 606. ISBN   978-1-60805-159-5.
  4. ↑ "Phase 2 Discovery, Inc. Acquires Drug in Clinical Development to Treat Sleep Disorders". Phase 2 Discovery, Inc. Acquires Drug in Clinical Development to Treat Sleep Disorders. Archived from the original on 2016-10-30. Retrieved 15 March 2015.
  5. ↑ "Tikvah Therapeutics Signs Agreement to Develop and Commercialize LY156735, a Second Generation Melatonin Agonist, for Circadian Rhythm and Sleep Disorders". Nasdaq Global Newswire (Press release). 2007-08-29.
  6. ↑ Kostiuk NV, Belyakova MB, Leshchenko DV, Zhigulina VV, Miniaev MV (2014). "Synthetic melatoninergic ligands: achievements and prospects". ISRN Biochemistry. 2014: 843478. doi: 10.1155/2014/843478 . PMC   4393004 . PMID   25937968.
  7. ↑ "Phase 2 Discovery, Inc. Receives Orphan Drug Designation From FDA For Synthetic Melatonin Analog PD-6735". BioSpace. 19 October 2005. Archived from the original on 4 March 2016.
  8. 1 2 3 4 Zlotos DP (2012). "Recent progress in the development of agonists and antagonists for melatonin receptors". Current Medicinal Chemistry. 19 (21): 3532–3549. doi:10.2174/092986712801323153. PMID   22680635.
  9. 1 2 3 4 5 Carocci A, Catalano A, Sinicropi MS (2014). "Melatonergic drugs in development". Clinical Pharmacology. 6: 127–137. doi: 10.2147/CPAA.S36600 . PMC   4172069 . PMID   25258560.
  10. ↑ Zlotos DP, Jockers R, Cecon E, Rivara S, Witt-Enderby PA (April 2014). "MT1 and MT2 melatonin receptors: ligands, models, oligomers, and therapeutic potential". Journal of Medicinal Chemistry. 57 (8): 3161–3185. doi:10.1021/jm401343c. PMID   24228714.
  11. 1 2 3 Hardeland R, Poeggeler B (September 2012). "Melatonin and synthetic melatonergic agonists: actions and metabolism in the central nervous system". Central Nervous System Agents in Medicinal Chemistry. 12 (3): 189–216. doi:10.2174/187152412802430129. PMID   22640220.
  12. 1 2 Chan KH, Hu Y, Ho MK, Wong YH (2013). "Characterization of substituted phenylpropylamides as highly selective agonists at the melatonin MT2 receptor". Current Medicinal Chemistry. 20 (2): 289–300. doi:10.2174/0929867311320020009. PMID   23131177.
  13. 1 2 3 4 5 6 7 8 Mulchahey JJ, Goldwater DR, Zemlan FP (August 2004). "A single blind, placebo controlled, across groups dose escalation study of the safety, tolerability, pharmacokinetics and pharmacodynamics of the melatonin analog beta-methyl-6-chloromelatonin". Life Sciences. 75 (15): 1843–1856. doi:10.1016/j.lfs.2004.03.023. PMID   15302228.
  14. 1 2 3 4 5 Nickelsen T, Samel A, Vejvoda M, Wenzel J, Smith B, Gerzer R (September 2002). "Chronobiotic effects of the melatonin agonist LY 156735 following a simulated 9h time shift: results of a placebo-controlled trial". Chronobiology International. 19 (5): 915–936. doi:10.1081/cbi-120014108. PMID   12405554. S2CID   10363563.
  15. 1 2 3 Cardinali DP, Srinivasan V, Brzezinski A, Brown GM (May 2012). "Melatonin and its analogs in insomnia and depression" (PDF). Journal of Pineal Research. 52 (4): 365–375. doi: 10.1111/j.1600-079x.2011.00962.x . PMID   21951153. S2CID   139480.
  16. 1 2 3 4 5 Zemlan FP, Mulchahey JJ, Scharf MB, Mayleben DW, Rosenberg R, Lankford A (March 2005). "The efficacy and safety of the melatonin agonist beta-methyl-6-chloromelatonin in primary insomnia: a randomized, placebo-controlled, crossover clinical trial". The Journal of Clinical Psychiatry. 66 (3): 384–390. doi:10.4088/jcp.v66n0316. PMID   15766306.
  17. 1 2 Turek FW, Gillette MU (November 2004). "Melatonin, sleep, and circadian rhythms: rationale for development of specific melatonin agonists". Sleep Medicine. 5 (6): 523–532. doi:10.1016/j.sleep.2004.07.009. PMID   15511698.
  18. ↑ Doghramji K (August 2007). "Melatonin and its receptors: a new class of sleep-promoting agents". Journal of Clinical Sleep Medicine. 3 (5 Suppl): S17–S23. doi:10.5664/jcsm.26932. PMC   1978320 . PMID   17824497.
  19. ↑ "PRESS RELEASE: Tikvah Therapeutics Signs Agreement with Phase 2 Discovery". fiercebiotech.com. 29 August 2007. Archived from the original on 2018-11-01. Retrieved 7 April 2015.
  20. ↑ Rivara S, Pala D, Bedini A, Spadoni G (April 2015). "Therapeutic uses of melatonin and melatonin derivatives: a patent review (2012 - 2014)". Expert Opinion on Therapeutic Patents. 25 (4): 425–441. doi:10.1517/13543776.2014.1001739. hdl: 11576/2623397 . PMID   25579320. S2CID   19644131.
  21. ↑ WO 2014010603,Watanabe K, Kawabata Y, Watanabe K, Yuyama N, Burgard S, Bruce E,"Pharmaceutical composition for treatment or prevention of stress urinary incontinence or mixed urinary incontinence, and screening method for compounds contained in the pharmaceutical composition",published 16 January 2014, assigned to Astellas Pharma Inc.
  22. ↑ Fee DB, Swartz KR, Scheff N, Roberts K, Gabbita P, Scheff S (June 2010). "Melatonin-analog, beta-methyl-6-chloromelatonin, supplementation in spinal cord injury". Brain Research. 1340: 81–85. doi:10.1016/j.brainres.2010.04.047. PMID   20420812. S2CID   27784753.
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