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Identification
NameRamelteon
Accession NumberDB00980  (APRD01213)
Typesmall molecule
Groupsapproved, investigational
Description

Ramelteon is the first in a new class of sleep agents that selectively binds to the melatonin receptors in the suprachiasmatic nucleus (SCN). It is used for insomnia, particularly delayed sleep onset. Ramelteon has not been shown to produce dependence and has shown no potential for abuse.

Structure
Thumb
SynonymsNot Available
SaltsNot Available
Brand names
NameCompany
RozeremNot Available
Brand mixturesNot Available
CategoriesNot Available
CAS number196597-26-9
WeightAverage: 259.3434
Monoisotopic: 259.157228921
Chemical FormulaC16H21NO2
InChI KeyYLXDSYKOBKBWJQ-LBPRGKRZSA-N
InChI
InChI=1S/C16H21NO2/c1-2-15(18)17-9-7-12-4-3-11-5-6-14-13(16(11)12)8-10-19-14/h5-6,12H,2-4,7-10H2,1H3,(H,17,18)/t12-/m0/s1
IUPAC Name
N-{2-[(8S)-1H,2H,6H,7H,8H-indeno[5,4-b]furan-8-yl]ethyl}propanamide
SMILES
CCC(=O)NCC[C@@H]1CCC2=C1C1=C(OCC1)C=C2
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassBenzofurans
SubclassNot Available
Direct parentBenzofurans
Alternative parentsIndanes; Alkyl Aryl Ethers; Benzene and Substituted Derivatives; Secondary Carboxylic Acid Amides; Carboxylic Acids; Polyamines; Enolates
Substituentsalkyl aryl ether; benzene; secondary carboxylic acid amide; carboxamide group; carboxylic acid derivative; enolate; carboxylic acid; ether; polyamine; amine; organonitrogen compound
Classification descriptionThis compound belongs to the benzofurans. These are organic compounds containing a benzene ring fused to a furan.
Pharmacology
IndicationFor the treatment of insomnia characterized by difficulty with sleep onset.
PharmacodynamicsRamelteon is the first selective melatonin agonist. It works by mimicking melatonin (MT), a naturally occuring hormone that is produced during the sleep period and thought to be responsible for the regulation of circadian rhythm underlying the normal sleep-wake cycle. Ramelteon has a high affinity for the MT1 and MT2 receptors. The MT1 and MT2 receptors are located in the brain's suprachiasmatic nuclei (SCN),which is known as the body's "master clock" because it regulates the 24-hour sleep-wake cycle. Ramelteon has an active metabolite that is less potent but circulates in higher concentrations than the parent compound. The metabolite also has weak affinity for the 5HT2b receptor.
Mechanism of actionRamelteon is a melatonin receptor agonist with both high affinity for melatonin MT1 and MT2 receptors, and lower selectivity for the MT3 receptor. Melatonin production is concurrent with nocturnal sleep, meaning that an increase in melatonin levels is related to the onset of self-reported sleepiness and an increase in sleep propensity. MT1 receptors are believed to be responsible for regulation of sleepiness and facilitation of sleep onset, and MT2 receptors are believed to mediate phase-shifting effects of melatonin on the circadian rhythm. While MT1 and MT2 receptors are associated with the sleep-wake cycle, MT3 has a completely different profile, and therefore is not likely to be involved in the sleep-wake cycle. Remelteon has no appreciable affinity for the gamma-aminobutyric acid (GABA) receptor complex or receptors that bind neuropeptides, cytokines, serotonin, dopamine, norepinephrine, acetylcholine, or opiates.
AbsorptionRapid, total absorption is at least 84%.
Volume of distribution
  • 73.6 L
Protein binding~82% (in human serum)
Metabolism

Hepatic

Route of eliminationFollowing oral administration of radiolabeled ramelteon, 84% of total radioactivity was excreted in urine and approximately 4% in feces, resulting in a mean recovery of 88%. Less than 0.1% of the dose was excreted in urine and feces as the parent compound.
Half life~1-2.6 hours
ClearanceNot Available
ToxicityNot Available
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 1.0
Blood Brain Barrier + 0.9934
Caco-2 permeable + 0.5893
P-glycoprotein substrate Substrate 0.5211
P-glycoprotein inhibitor I Non-inhibitor 0.8548
P-glycoprotein inhibitor II Non-inhibitor 0.7877
Renal organic cation transporter Non-inhibitor 0.6381
CYP450 2C9 substrate Non-substrate 0.7876
CYP450 2D6 substrate Non-substrate 0.6392
CYP450 3A4 substrate Substrate 0.512
CYP450 1A2 substrate Inhibitor 0.7314
CYP450 2C9 substrate Non-inhibitor 0.6471
CYP450 2D6 substrate Non-inhibitor 0.5916
CYP450 2C19 substrate Inhibitor 0.8314
CYP450 3A4 substrate Non-inhibitor 0.9196
CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.7763
Ames test Non AMES toxic 0.7016
Carcinogenicity Non-carcinogens 0.8206
Biodegradation Ready biodegradable 0.6635
Rat acute toxicity 2.1034 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.7898
hERG inhibition (predictor II) Inhibitor 0.5
Pharmacoeconomics
Manufacturers
  • Takeda global research development center inc
Packagers
Dosage forms
FormRouteStrength
TabletOral
Prices
Unit descriptionCostUnit
Rozerem 8 mg tablet5.17USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States60342391999-07-222019-07-22
Properties
Statesolid
Experimental Properties
PropertyValueSource
logP2.4Not Available
Predicted Properties
PropertyValueSource
water solubility1.64e-02 g/lALOGPS
logP3.03ALOGPS
logP2.57ChemAxon
logS-4.2ALOGPS
pKa (strongest acidic)15.82ChemAxon
pKa (strongest basic)-0.4ChemAxon
physiological charge0ChemAxon
hydrogen acceptor count2ChemAxon
hydrogen donor count1ChemAxon
polar surface area38.33ChemAxon
rotatable bond count4ChemAxon
refractivity75.52ChemAxon
polarizability29.99ChemAxon
number of rings3ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleYesChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Vinod Kumar Kansal, Dhirenkumar N. Mistry, Sanjay L. Vasoya, “Intermediates and processes for the synthesis of Ramelteon.” U.S. Patent US20080242877, issued October 02, 2008.

US20080242877
General Reference
  1. Karim A, Tolbert D, Cao C: Disposition kinetics and tolerance of escalating single doses of ramelteon, a high-affinity MT1 and MT2 melatonin receptor agonist indicated for treatment of insomnia. J Clin Pharmacol. 2006 Feb;46(2):140-8. Pubmed
  2. Miyamoto M: Pharmacology of ramelteon, a selective MT1/MT2 receptor agonist: a novel therapeutic drug for sleep disorders. CNS Neurosci Ther. 2009 Winter;15(1):32-51. Pubmed
  3. Pandi-Perumal SR, Srinivasan V, Spence DW, Moscovitch A, Hardeland R, Brown GM, Cardinali DP: Ramelteon: a review of its therapeutic potential in sleep disorders. Adv Ther. 2009 Jun;26(6):613-26. Epub 2009 Jun 30. Pubmed
  4. Borja NL, Daniel KL: Ramelteon for the treatment of insomnia. Clin Ther. 2006 Oct;28(10):1540-55. Pubmed
  5. Roth T, Stubbs C, Walsh JK: Ramelteon (TAK-375), a selective MT1/MT2-receptor agonist, reduces latency to persistent sleep in a model of transient insomnia related to a novel sleep environment. Sleep. 2005 Mar 1;28(3):303-7. Pubmed
  6. Simpson D, Curran MP: Ramelteon: a review of its use in insomnia. Drugs. 2008;68(13):1901-19. Pubmed
External Links
ResourceLink
PubChem Compound208902
PubChem Substance46505923
ChemSpider181000
BindingDB50118470
Therapeutic Targets DatabaseDAP000070
PharmGKBPA164744896
IUPHAR1356
Guide to Pharmacology1356
RxListhttp://www.rxlist.com/cgi/generic4/rozerem.htm
Drugs.comhttp://www.drugs.com/cdi/ramelteon.html
WikipediaRamelteon
ATC CodesNot Available
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelshow(2.36 MB)
MSDSNot Available
Interactions
Drug Interactions
Drug
AtazanavirAtazanavir increases levels/toxicity of ramelteon
CiprofloxacinCiprofloxacin increases levels/toxicity of ramelteon
EnoxacinEnoxacin increases levels/toxicity of ramelteon
FluconazoleFluconazole may increase the serum levels and toxcity of ramelteon.
FluvoxamineFluvoxamine may increase the serum level and toxicity of ramelteon.
KetoconazoleKetoconazole may increase the serum levels and toxicity of ramelteon.
MexiletineMexiletine increases levels/toxicity of ramelteon
RifampicinRifampin reduces the levels/effect of ramelteon
TacrineTacrine increases levels/toxicity of ramelteon
ThiabendazoleThiabendazole increases levels/toxicity of ramelteon
TriprolidineThe CNS depressants, Triprolidine and Ramelteon, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy.
ZileutonZileuton increases levels/toxicity of ramelteon
Food Interactions
  • Avoid alcohol.
  • Do not take with or immediately after a high-fat meal.

Targets

1. Melatonin receptor type 1A

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: multitarget

Components

Name UniProt ID Details
Melatonin receptor type 1A P48039 Details

References:

  1. Kato K, Hirai K, Nishiyama K, Uchikawa O, Fukatsu K, Ohkawa S, Kawamata Y, Hinuma S, Miyamoto M: Neurochemical properties of ramelteon (TAK-375), a selective MT1/MT2 receptor agonist. Neuropharmacology. 2005 Feb;48(2):301-10. Pubmed
  2. Karim A, Tolbert D, Cao C: Disposition kinetics and tolerance of escalating single doses of ramelteon, a high-affinity MT1 and MT2 melatonin receptor agonist indicated for treatment of insomnia. J Clin Pharmacol. 2006 Feb;46(2):140-8. Pubmed
  3. Greenblatt DJ, Harmatz JS, Karim A: Age and gender effects on the pharmacokinetics and pharmacodynamics of ramelteon, a hypnotic agent acting via melatonin receptors MT1 and MT2. J Clin Pharmacol. 2007 Apr;47(4):485-96. Pubmed
  4. Roth T, Stubbs C, Walsh JK: Ramelteon (TAK-375), a selective MT1/MT2-receptor agonist, reduces latency to persistent sleep in a model of transient insomnia related to a novel sleep environment. Sleep. 2005 Mar 1;28(3):303-7. Pubmed
  5. Miyamoto M: Effect of ramelteon (TAK-375), a selective MT1/MT2 receptor agonist, on motor performance in mice. Neurosci Lett. 2006 Jul 24;402(3):201-4. Epub 2006 May 24. Pubmed
  6. Ramelteon: TAK 375. Drugs R D. 2005;6(3):186-8. Pubmed
  7. Miyamoto M: Pharmacology of ramelteon, a selective MT1/MT2 receptor agonist: a novel therapeutic drug for sleep disorders. CNS Neurosci Ther. 2009 Winter;15(1):32-51. Pubmed
  8. Miyamoto M: [A novel therapeutic drug: ramelteon] Nippon Rinsho. 2009 Aug;67(8):1595-600. Pubmed
  9. Pandi-Perumal SR, Srinivasan V, Spence DW, Moscovitch A, Hardeland R, Brown GM, Cardinali DP: Ramelteon: a review of its therapeutic potential in sleep disorders. Adv Ther. 2009 Jun;26(6):613-26. Epub 2009 Jun 30. Pubmed
  10. Borja NL, Daniel KL: Ramelteon for the treatment of insomnia. Clin Ther. 2006 Oct;28(10):1540-55. Pubmed
  11. Johnson MW, Suess PE, Griffiths RR: Ramelteon: a novel hypnotic lacking abuse liability and sedative adverse effects. Arch Gen Psychiatry. 2006 Oct;63(10):1149-57. Pubmed
  12. Zammit G, Erman M, Wang-Weigand S, Sainati S, Zhang J, Roth T: Evaluation of the efficacy and safety of ramelteon in subjects with chronic insomnia. J Clin Sleep Med. 2007 Aug 15;3(5):495-504. Pubmed
  13. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

2. Melatonin receptor type 1B

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: multitarget

Components

Name UniProt ID Details
Melatonin receptor type 1B P49286 Details

References:

  1. Kato K, Hirai K, Nishiyama K, Uchikawa O, Fukatsu K, Ohkawa S, Kawamata Y, Hinuma S, Miyamoto M: Neurochemical properties of ramelteon (TAK-375), a selective MT1/MT2 receptor agonist. Neuropharmacology. 2005 Feb;48(2):301-10. Pubmed
  2. Karim A, Tolbert D, Cao C: Disposition kinetics and tolerance of escalating single doses of ramelteon, a high-affinity MT1 and MT2 melatonin receptor agonist indicated for treatment of insomnia. J Clin Pharmacol. 2006 Feb;46(2):140-8. Pubmed
  3. Greenblatt DJ, Harmatz JS, Karim A: Age and gender effects on the pharmacokinetics and pharmacodynamics of ramelteon, a hypnotic agent acting via melatonin receptors MT1 and MT2. J Clin Pharmacol. 2007 Apr;47(4):485-96. Pubmed
  4. Roth T, Stubbs C, Walsh JK: Ramelteon (TAK-375), a selective MT1/MT2-receptor agonist, reduces latency to persistent sleep in a model of transient insomnia related to a novel sleep environment. Sleep. 2005 Mar 1;28(3):303-7. Pubmed
  5. Miyamoto M: Effect of ramelteon (TAK-375), a selective MT1/MT2 receptor agonist, on motor performance in mice. Neurosci Lett. 2006 Jul 24;402(3):201-4. Epub 2006 May 24. Pubmed
  6. Ramelteon: TAK 375. Drugs R D. 2005;6(3):186-8. Pubmed
  7. Miyamoto M: Pharmacology of ramelteon, a selective MT1/MT2 receptor agonist: a novel therapeutic drug for sleep disorders. CNS Neurosci Ther. 2009 Winter;15(1):32-51. Pubmed
  8. Miyamoto M: [A novel therapeutic drug: ramelteon] Nippon Rinsho. 2009 Aug;67(8):1595-600. Pubmed
  9. Pandi-Perumal SR, Srinivasan V, Spence DW, Moscovitch A, Hardeland R, Brown GM, Cardinali DP: Ramelteon: a review of its therapeutic potential in sleep disorders. Adv Ther. 2009 Jun;26(6):613-26. Epub 2009 Jun 30. Pubmed
  10. Borja NL, Daniel KL: Ramelteon for the treatment of insomnia. Clin Ther. 2006 Oct;28(10):1540-55. Pubmed
  11. Johnson MW, Suess PE, Griffiths RR: Ramelteon: a novel hypnotic lacking abuse liability and sedative adverse effects. Arch Gen Psychiatry. 2006 Oct;63(10):1149-57. Pubmed
  12. Zammit G, Erman M, Wang-Weigand S, Sainati S, Zhang J, Roth T: Evaluation of the efficacy and safety of ramelteon in subjects with chronic insomnia. J Clin Sleep Med. 2007 Aug 15;3(5):495-504. Pubmed
  13. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

Enzymes

1. Cytochrome P450 1A2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 1A2 P05177 Details

References:

  1. Obach RS, Ryder TF: Metabolism of ramelteon in human liver microsomes and correlation with the effect of fluvoxamine on ramelteon pharmacokinetics. Drug Metab Dispos. 2010 Aug;38(8):1381-91. Epub 2010 May 17. Pubmed
  2. Obach RS, Ryder TF: Metabolism of ramelteon in human liver microsomes and correlation with the effect of fluvoxamine on ramelteon pharmacokinetics. Drug Metab Dispos. 2010 Aug;38(8):1381-91. Epub 2010 May 17. Pubmed

2. Cytochrome P450 2C19

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2C19 P33261 Details

References:

  1. Obach RS, Ryder TF: Metabolism of ramelteon in human liver microsomes and correlation with the effect of fluvoxamine on ramelteon pharmacokinetics. Drug Metab Dispos. 2010 Aug;38(8):1381-91. Epub 2010 May 17. Pubmed

3. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

References:

  1. Obach RS, Ryder TF: Metabolism of ramelteon in human liver microsomes and correlation with the effect of fluvoxamine on ramelteon pharmacokinetics. Drug Metab Dispos. 2010 Aug;38(8):1381-91. Epub 2010 May 17. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:12