LY-156,735 and TIK-301: Difference between pages

{{Short description|Chemical compound}}

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| Verifiedfields = changed

| Watchedfields = changed

| verifiedrevid = 451552925

| legal_status = Investigational

| routes_of_administration = Oral

| elimination_half-life = 1 hour

| IUPHAR_ligand = 1351

| CAS_number_Ref = {{cascite|correct|??}}

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = 3ZX95B1ZWK

| PubChem = 219018

| DrugBank =

| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}

| ChemSpiderID = 189853

| ChEMBL = 4079759

| synonyms = Beta-methyl-6-chloromelatonin; LY-156735; PD-6735

| C=14 | H=17 | Cl=1 | N=2 | O=2

| smiles = C[C@@H](CNC(=O)C)c1c[nH]c2c1cc(c(c2)Cl)OC

| StdInChI_Ref = {{stdinchicite|changed|chemspider}}

| StdInChI = 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

| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}

| StdInChIKey = RKHCTAKUYDTFHE-QMMMGPOBSA-N

'''TIK-301''' ('''LY-156735''') is an [[agonist]] for the [[melatonin receptor]]s MT₁ and MT₂ that is under development for the treatment of [[insomnia]] and other sleep disorders.<ref>{{cite web| url = https://www.chemdrug.com/databases/8_0_unnmipljvsnjrcxn.html| url-status = dead| archive-url = https://web.archive.org/web/20090927141606/https://www.chemdrug.com/databases/8_0_unnmipljvsnjrcxn.html| archive-date = 2009-09-27| title = PD-6735, LY-156735,118702-11-7,C14-H17-Cl-N2-O2,N-[2(R)-(6-C--药物合成数据库}} </ref> 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 agonist]]s as [[ramelteon]] and [[tasimelteon]].

==History and development==

TIK-301 was first developed at [[Eli Lilly and Company]] in [[Indianapolis]], Indiana, as LY-156735. In 2002, it was licensed by Phase 2 Discovery for further commercialization and worldwide development as PD-6735.<ref name="Rivara SAR" /><ref name="Frontiers eBook Background info.">{{cite book| vauthors = Mody S, Hu Y, Ho MK, Wong YH |title=Frontiers in CNS Drug Discovery|publisher=Bentham eBooks|isbn=978-1-60805-159-5|page=606|date=2011-08-12}}</ref> In July 2007, the open [[Investigational New Drug|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.<ref name="Company Acq">{{cite web|title=Phase 2 Discovery, Inc. Acquires Drug in Clinical Development to Treat Sleep Disorders|url=https://www.prnewswire.com/news-releases/phase-2-discovery-inc-acquires-drug-in-clinical-development-to-treat-sleep-disorders-75490887.html | url-status = dead | archive-url = https://web.archive.org/web/20161030141326/https://www.prnewswire.com/news-releases/phase-2-discovery-inc-acquires-drug-in-clinical-development-to-treat-sleep-disorders-75490887.html | archive-date = 2016-10-30 |website = Phase 2 Discovery, Inc. Acquires Drug in Clinical Development to Treat Sleep Disorders|access-date=15 March 2015}}</ref><ref name="Tikvah Press Release">{{cite press release|title=Tikvah Therapeutics Signs Agreement to Develop and Commercialize LY156735, a Second Generation Melatonin Agonist, for Circadian Rhythm and Sleep Disorders|url=https://globenewswire.com/news-release/2007/08/29/364903/125733/en/Tikvah-Therapeutics-Signs-Agreement-to-Develop-and-Commercialize-LY156735-a-Second-Generation-Melatonin-Agonist-for-Circadian-Rhythm-and-Sleep-Disorders.html|website=Nasdaq Global Newswire|date=2007-08-29}}</ref><ref>{{cite journal | vauthors = Kostiuk NV, Belyakova MB, Leshchenko DV, Zhigulina VV, Miniaev MV | title = Synthetic melatoninergic ligands: achievements and prospects | journal = ISRN Biochemistry | volume = 2014 | pages = 843478 | date = 2014 | pmid = 25937968 | pmc = 4393004 | doi = 10.1155/2014/843478 | doi-access = free }}</ref> 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.<ref name="Rivara SAR" /> In 2004, TIK-301 was designated an [[orphan drug]] by the FDA.<ref name="Rivara SAR" /><ref name="Press Release Orphan Drug">{{cite web|title=Phase 2 Discovery, Inc. Receives Orphan Drug Designation From FDA For Synthetic Melatonin Analog PD-6735 | date = 19 October 2005 | work =BioSpace |url=https://www.biospace.com/News/1-receives-orphan-drug-designation-from-2-for/16288720 | archive-url = https://web.archive.org/web/20160304115303/https://www.biospace.com/News/1-receives-orphan-drug-designation-from-2-for/16288720 | archive-date = 4 March 2016 }}</ref>

==Pharmacodynamics==

TIK-301 is a high affinity nonselective MT₁/MT₂ agonist.<ref name="Zlotos recent Progress">{{cite journal | vauthors = Zlotos DP | title = Recent progress in the development of agonists and antagonists for melatonin receptors | journal = Current Medicinal Chemistry | volume = 19 | issue = 21 | pages = 3532–3549 | date = 2012 | pmid = 22680635 | doi = 10.2174/092986712801323153 }}</ref> Studies show that it is more potent and more effective than [[melatonin]]. Its affinity for MT₁ is similar to that of melatonin (pK_i =10.38, K_i=81pM) and its affinity for MT₂ is slightly higher (pK_i=10.38, K_i= 42pM).<ref name="Rivara SAR">{{cite journal | vauthors = Rivara S, Mor M, Bedini A, Spadoni G, Tarzia G | title = Melatonin receptor agonists: SAR and applications to the treatment of sleep-wake disorders | journal = Current Topics in Medicinal Chemistry | volume = 8 | issue = 11 | pages = 954–968 | date = 2008 | pmid = 18673165 | doi = 10.2174/156802608784936719 }}</ref><ref name="Zlotos recent Progress" /><ref name=Carocci>{{cite journal | vauthors = Carocci A, Catalano A, Sinicropi MS | title = Melatonergic drugs in development | journal = Clinical Pharmacology | volume = 6 | pages = 127–137 | date = 2014 | pmid = 25258560 | pmc = 4172069 | doi = 10.2147/CPAA.S36600 | doi-access = free }}</ref><ref name="Zlotos et al 2014">{{cite journal | vauthors = Zlotos DP, Jockers R, Cecon E, Rivara S, Witt-Enderby PA | title = MT1 and MT2 melatonin receptors: ligands, models, oligomers, and therapeutic potential | journal = Journal of Medicinal Chemistry | volume = 57 | issue = 8 | pages = 3161–3185 | date = April 2014 | pmid = 24228714 | doi = 10.1021/jm401343c }}</ref><ref name="Hardeland Poeg">{{cite journal | vauthors = Hardeland R, Poeggeler B | title = Melatonin and synthetic melatonergic agonists: actions and metabolism in the central nervous system | journal = Central Nervous System Agents in Medicinal Chemistry | volume = 12 | issue = 3 | pages = 189–216 | date = September 2012 | pmid = 22640220 | doi = 10.2174/187152412802430129 }}</ref> This [[enantiomer]] had higher affinity for the binding site compared to the racemic mixture.<ref name="Rivara SAR" /> The MT₁/MT₂ K_i ratio is 1.9.<ref name="Chan Wong 2013" /> This slight preference for MT₂ receptor is common among melatonin derivatives with chlorine.<ref name=Carocci /><ref name="Chan Wong 2013">{{cite journal | vauthors = Chan KH, Hu Y, Ho MK, Wong YH | title = Characterization of substituted phenylpropylamides as highly selective agonists at the melatonin MT2 receptor | journal = Current Medicinal Chemistry | volume = 20 | issue = 2 | pages = 289–300 | date = 2013 | pmid = 23131177 | doi = 10.2174/0929867311320020009 }}</ref> 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.<ref name=Mulchahey /> The [[EC50|EC₅₀]] of TIK-301 is 0.0479nM, compared to 0.063nM for melatonin.<ref name="Zlotos recent Progress" /> It also acts as an antagonist at [[serotonin]] receptors [[5-HT2B|5-HT_2B]] and [[5-HT2C|5-HT_2C]].<ref name=Carocci />

==Pharmacokinetics==

TIK-301 is administered orally.<ref name="Nickelsen et al">{{cite journal | vauthors = Nickelsen T, Samel A, Vejvoda M, Wenzel J, Smith B, Gerzer R | title = Chronobiotic effects of the melatonin agonist LY 156735 following a simulated 9h time shift: results of a placebo-controlled trial | journal = Chronobiology International | volume = 19 | issue = 5 | pages = 915–936 | date = September 2002 | pmid = 12405554 | doi = 10.1081/cbi-120014108 | s2cid = 10363563 }}</ref> Compared to melatonin, it has nine times greater [[bioavailability]] and six times greater [[Area under the curve (pharmacokinetics)|area under the curve]] (AUC), which means the body retains more of an administered dose.<ref name=Mulchahey>{{cite journal | vauthors = Mulchahey JJ, Goldwater DR, Zemlan FP | title = 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 | journal = Life Sciences | volume = 75 | issue = 15 | pages = 1843–1856 | date = August 2004 | pmid = 15302228 | doi = 10.1016/j.lfs.2004.03.023 }}</ref><ref name="Nickelsen et al" /> 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.<ref name=Mulchahey /> Plasma concentrations increased rapidly and peaked at 1 hour after the dose, independent of dose size.<ref name=Mulchahey /> TIK-301's [[half-life]] is about 1 hour.<ref name=Carocci /><ref name=Mulchahey /> This extended half-life may be partially due to the chlorine in its structure.<ref name="Hardeland Poeg" /> Elimination constants depended on dose, 20&nbsp;mg dose had a different elimination constant from all other doses above 35&nbsp;mg.<ref name=Mulchahey />

==Treatment==

TIK-301 is intended to be a take-as-need drug for [[primary insomnia]], [[circadian rhythm disorder]]s, depression, as well as sleep disorders in blind individuals and can be used to alleviate neuroleptic-induced tardive dyskinesia in schizophrenia patients.<ref name=Cardinali>{{cite journal | vauthors = Cardinali DP, Srinivasan V, Brzezinski A, Brown GM | title = Melatonin and its analogs in insomnia and depression | journal = Journal of Pineal Research | volume = 52 | issue = 4 | pages = 365–375 | date = May 2012 | pmid = 21951153 | doi = 10.1111/j.1600-079x.2011.00962.x | s2cid = 139480 | doi-access = free | url = https://repositorio.uca.edu.ar/bitstream/123456789/1636/1/melatonin-analogs-insomnia-depression-cardinali.pdf }}</ref> In a [[Phase I clinical trial|phase I]] clinical trial, TIK-301 was shown to be effective as a chronobiotic at a dose of 5&nbsp;mg/L, but not in lower doses.<ref name="Nickelsen et al" /> In a [[Phase II clinical trial|phase II]] trial for [[primary insomnia]], patients experienced objective and subjective improvements in sleep latency at 20&nbsp;mg (31% improvement), 50&nbsp;mg (32%) and 100&nbsp;mg (41%) doses.<ref name=Zemlan /> The sleep latency improvement at the 100&nbsp;mg dose is comparable to FDA approved [[zolpidem]]'s effects.<ref name=Zemlan /> Surprisingly, it showed no such effects in healthy patients when taken before bed.<ref name=Turek>{{cite journal | vauthors = Turek FW, Gillette MU | title = Melatonin, sleep, and circadian rhythms: rationale for development of specific melatonin agonists | journal = Sleep Medicine | volume = 5 | issue = 6 | pages = 523–532 | date = November 2004 | pmid = 15511698 | doi = 10.1016/j.sleep.2004.07.009 }}</ref> In a test of phase shifted circadian cycle, TIK-301 showed efficacy in readjusting phase shifts in all physiological systems.<ref name="Nickelsen et al" /><ref name="Doghramji Overview Paper">{{cite journal | vauthors = Doghramji K | title = Melatonin and its receptors: a new class of sleep-promoting agents | journal = Journal of Clinical Sleep Medicine | volume = 3 | issue = 5 Suppl | pages = S17–S23 | date = August 2007 | pmid = 17824497 | pmc = 1978320 | doi = 10.5664/jcsm.26932 }}</ref> 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&nbsp;mg or 200&nbsp;mg.<ref name="Hardeland Poeg" />

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]].<ref name="Zlotos recent Progress" /><ref name=Carocci /><ref>{{cite web |title=PRESS RELEASE: Tikvah Therapeutics Signs Agreement with Phase 2 Discovery | date = 29 August 2007 |url=https://www.fiercebiotech.com/press-releases/press-release-tikvah-therapeutics-signs-agreement-phase-2-discovery | url-status = dead | archive-url = https://web.archive.org/web/20181101150005/https://www.fiercebiotech.com/biotech/press-release-tikvah-therapeutics-signs-agreement-phase-2-discovery | archive-date = 2018-11-01 |access-date=7 April 2015 | work = fiercebiotech.com }}</ref> TIK-301 has also been considered for use in patients with [[mild cognitive impairment]] (MCI) because of sleep disorder prevalence.<ref name=Cardinali /> 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.<ref name="Rivara Patent">{{cite journal | vauthors = Rivara S, Pala D, Bedini A, Spadoni G | title = Therapeutic uses of melatonin and melatonin derivatives: a patent review (2012 - 2014) | journal = Expert Opinion on Therapeutic Patents | volume = 25 | issue = 4 | pages = 425–441 | date = April 2015 | pmid = 25579320 | doi = 10.1517/13543776.2014.1001739 | hdl-access = free | s2cid = 19644131 | hdl = 11576/2623397 }}</ref><ref name="Urinary Inton TIK301">{{cite patent | country = WO | number = 2014010603 | title = Pharmaceutical composition for treatment or prevention of stress urinary incontinence or mixed urinary incontinence, and screening method for compounds contained in the pharmaceutical composition | inventor = Watanabe K, Kawabata Y, Watanabe K, Yuyama N, Burgard S, Bruce E | assign1 = Astellas Pharma Inc.| pubdate = 16 January 2014 }}</ref>

It is also seen as a potential therapeutic agent for spinal cord injury (SCI); in low doses (10&nbsp;mg/kg) it was seen to be benefit in rats after SCI, but in higher doses (100&nbsp;mg/kg), it proved toxic.<ref name="Fee SCI">{{cite journal | vauthors = Fee DB, Swartz KR, Scheff N, Roberts K, Gabbita P, Scheff S | title = Melatonin-analog, beta-methyl-6-chloromelatonin, supplementation in spinal cord injury | journal = Brain Research | volume = 1340 | pages = 81–85 | date = June 2010 | pmid = 20420812 | doi = 10.1016/j.brainres.2010.04.047 | s2cid = 27784753 }}</ref>

==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.<ref name="Nickelsen et al" /><ref name=Zemlan>{{cite journal | vauthors = Zemlan FP, Mulchahey JJ, Scharf MB, Mayleben DW, Rosenberg R, Lankford A | title = The efficacy and safety of the melatonin agonist beta-methyl-6-chloromelatonin in primary insomnia: a randomized, placebo-controlled, crossover clinical trial | journal = The Journal of Clinical Psychiatry | volume = 66 | issue = 3 | pages = 384–390 | date = March 2005 | pmid = 15766306 | doi = 10.4088/jcp.v66n0316 }}</ref>

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.<ref name=Zemlan /> A few patients reported cases of [[somnolence]] in clinical trials, which is consistent with the drug's soporific effects.<ref name=Mulchahey />

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.<ref name=Mulchahey /><ref name=Cardinali /><ref name=Zemlan /><ref name=Turek />

{{Reflist|30em}}

{{Serotonergics}}

{{Tryptamines}}

[[Category:5-HT2B antagonists]]

[[Category:5-HT2C antagonists]]

[[Category:Chloroarenes]]

[[Category:Melatonin receptor agonists]]