TIK-301

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TIK-301
Clinical data
Other namesBeta-methyl-6-chloromelatonin; LY-156735; PD-6735
Routes of
administration		Oral
Legal status
Legal status
  • Investigational
Pharmacokinetic data
Elimination half-life1 hour
Identifiers
  • N-[(2R)-(6-Chloro-5-methoxy-1H-indol-3-yl)propyl]acetamide
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 ☒N
  • Key:RKHCTAKUYDTFHE-QMMMGPOBSA-N ☒N
 ☒NcheckY (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.

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.

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, 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]

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. ^
    PMID 18673165
    .
  3. 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. 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. ^
    PMID 22680635
    .
  9. ^
    PMID 25258560
    .
  10. PMID 24228714
    .
  11. ^
    PMID 22640220
    .
  12. ^
    PMID 23131177
    .
  13. ^
    PMID 15302228
    .
  14. ^
    S2CID 10363563
    .
  15. ^
    S2CID 139480
    .
  16. ^
    PMID 15766306
    .
  17. ^
    PMID 15511698
    .
  18. 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. 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. S2CID 27784753
    .
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