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TIK-301

April 12, 2024

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.

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
CAS Number
  • 118702-11-7 Y
PubChem CID
  • 219018
IUPHAR/BPS
  • 1351
ChemSpider
  • 189853 N
UNII
  • 3ZX95B1ZWK
ChEMBL
  • ChEMBL4079759
CompTox Dashboard (EPA)
  • DTXSID70922760
Chemical and physical data
FormulaC14H17ClN2O2
Molar mass280.75 g·mol−1
3D model (JSmol)
  • Interactive image
  • 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
 NY (what is this?)  (verify)

History and development edit

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 edit

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 edit

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 edit

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 edit

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 edit

  1. ^ . Archived from the original on 2009-09-27.
  2. ^ a b c d e 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. 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. ^ . BioSpace. 19 October 2005. Archived from the original on 4 March 2016.
  8. ^ a b c d 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. ^ a b c d e 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. ^ a b c 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. ^ a b 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. ^ a b c d e f g h 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. ^ a b c d e 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. ^ a b c 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. ^ a b c d e 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. ^ a b 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. ^ . 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.

April 12, 2024
156735, agonist, melatonin, receptors, that, under, development, treatment, insomnia, other, sleep, disorders, agonist, action, receptors, suprachiasmatic, nucleus, brain, enables, action, chronobiotic, same, class, melatonin, receptor, agonists, ramelteon, ta. 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 TIK 301Clinical dataOther namesBeta methyl 6 chloromelatonin LY 156735 PD 6735Routes ofadministrationOralLegal statusLegal statusInvestigationalPharmacokinetic dataElimination half life1 hourIdentifiersIUPAC name N 2R 6 Chloro 5 methoxy 1H indol 3 yl propyl acetamideCAS Number118702 11 7 YPubChem CID219018IUPHAR BPS1351ChemSpider189853 NUNII3ZX95B1ZWKChEMBLChEMBL4079759CompTox Dashboard EPA DTXSID70922760Chemical and physical dataFormulaC 14H 17Cl N 2O 2Molar mass280 75 g mol 13D model JSmol Interactive imageSMILES C C H CNC O C c1c nH c2c1cc c c2 Cl OCInChI 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 NKey RKHCTAKUYDTFHE QMMMGPOBSA N N N Y what is this verify Contents 1 History and development 2 Pharmacodynamics 3 Pharmacokinetics 4 Treatment 5 Side effects 6 ReferencesHistory and development editTIK 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 editTIK 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 editTIK 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 editTIK 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 editThere 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 edit 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 a b c d e 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 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 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 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 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 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 a b c d 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 a b c d e 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 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 a b c 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 a b 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 a b c d e f g h 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 a b c d e 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 a b c 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 a b c d e 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 a b 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 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 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 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 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 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 Retrieved from https en wikipedia org w index php title TIK 301 amp oldid 1203026346, wikipedia, wiki, book, books, library,

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