AGOMELATINE

Iupac Name：N-[2-(7-methoxynaphthalen-1-yl)ethyl]acetamide

Molecular Weight：243.306

Modify Date.: 2022-11-25 02:22

Introduction:

Agomelatine is a competitive antagonist of human and porcine serotonin (5-HT2C) receptors (pKi = 6.2 and 6.4, respectively) as well as human 5-HT2B receptors (pKi = 6.6). IC50 value: 6.2 (pKi, 5-HT2c); 6.6 (pKi, 5-HT2b)Target: 5-HT2C Receptor; 5-HT2B receptorIt is classified as a norepinephrine-dopamine disinhibitor (NDDI) due to its antagonism of the 5-HT2C receptor. Activation of 5-HT2C receptors by serotonin inhibits dopamine and norepinephrine release. Antagonism of 5-HT2C results in

Solid

Agomelatine is a member of acetamides.|Agomelatine is structurally closely related to melatonin. Agomelatine is a potent agonist at melatonin receptors and an antagonist at serotonin-2C (5-HT2C) receptors, tested in an animal model of depression. Agomelatine was developed in Europe by Servier Laboratories Ltd. and submitted to the European Medicines Agency (EMA) in 2005. The Committee for Medical Products for Human Use (CHMP) recommended refusal of marketing authorization on 27 July 2006. The major concern was that efficacy had not been sufficiently shown. In 2006 Servier sold the rights to develop Agomelatine in the US to Novartis. The development for the US market was discontinued in October 2011. It is currently sold in Australia under the Valdoxan trade name.

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1. Names and Identifiers

: 1.1 Name; AGOMELATINE; 1.2 Synonyms; Acetamide, N-(2-(7-methoxy-1-naphthalenyl)ethyl)- Acetamide, N-[2-(7-methoxy-1-naphthalenyl)ethyl]- Aglomelatine AGOMELATIN AgoMelatine(S-20098,Valdoxan) CS-1963 MELITOR N-(2-(7-Methoxynaphthalen-1-yl)ethyl)acetamide N-[2-(7-Methoxy-1-naphthalenyl)ethyl]acetamide N-[2-(7-Methoxy-1-naphthalenyl)ethyl]-acetamide S-20098 N-[2-(7-Methoxy-1-naphthyl)ethyl]acetamide S 20098 S20098,N-[2-(7-Methoxynaphth-1-yl)ethyl]acetamide THYMANAX Unii-137R1N49ad VALDOXAN; View all

1.3 CAS No.: 138112-76-2

1.4 CID: 82148

1.5 EINECS(EC#): 1312995-182-4

1.6 Molecular Formula: C15H17NO2 (isomer)

1.7 Inchi: InChI=1S/C15H17NO2/c1-11(17)16-9-8-13-5-3-4-12-6-7-14(18-2)10-15(12)13/h3-7,10H,8-9H2,1-2H3,(H,16,17)

1.8 InChIkey: YJYPHIXNFHFHND-UHFFFAOYSA-N

1.9 Canonical Smiles: CC(=O)NCCC1=CC=CC2=C1C=C(C=C2)OC

1.10 Isomers Smiles: CC(=O)NCCC1=CC=CC2=C1C=C(C=C2)OC

2. Properties

2.1 Density: 1.109

2.1 Melting point: 107-109°C

2.1 Boiling point: 478.8 °C at 760 mmHg

2.1 Refractive index: 1.582

2.1 Flash Point: 243.4 °C

2.1 Precise Quality: 243.12600

2.1 PSA: 38.33000

2.1 logP: 2.91790

2.1 Solubility: DMSO: >50mg/mL

2.2 Appearance: white solid

2.3 Storage: -20°C Freezer

2.4 Chemical Properties: White Solid

2.5 Color/Form: Powder

2.6 Physical: Solid

2.7 pKa: 16.17±0.46(Predicted)

2.8 Water Solubility: 7.76e-03 g/L

2.9 StorageTemp: 2-8°C

3. Use and Manufacturing

3.1 GHS Classification: Signal: Warning
GHS Hazard Statements
Aggregated GHS information provided by 33 companies from 6 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Reported as not meeting GHS hazard criteria by 1 of 33 companies. For more detailed information, please visit ECHA C&L website

Of the 5 notification(s) provided by 32 of 33 companies with hazard statement code(s):

H315 (21.88%): Causes skin irritation [Warning Skin corrosion/irritation]
H319 (18.75%): Causes serious eye irritation [Warning Serious eye damage/eye irritation]
H335 (15.62%): May cause respiratory irritation [Warning Specific target organ toxicity, single exposure; Respiratory tract irritation]
H400 (93.75%): Very toxic to aquatic life [Warning Hazardous to the aquatic environment, acute hazard]

Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown.

Precautionary Statement Codes
P261, P264, P271, P273, P280, P302+P352, P304+P340, P305+P351+P338, P312, P321, P332+P313, P337+P313, P362, P391, P403+P233, P405, and P501; View all

3.2 Usage: Melatonin drugs.

4. Safety and Handling

4.1 Symbol: GHS09

4.1 Hazard Codes: N

4.1 Signal Word: Warning

4.1 Risk Statements: 50

4.1 Safety Statements: 61

4.1 Hazard Declaration: H400

4.1 RIDADR: UN 3077 9 / PGIII

4.1 Caution Statement: P273

4.1 WGK Germany: 3

4.1 RTECS: AC5956323

4.1 Specification: Agomelatine , its CAS NO. is 138112-76-2, the synonyms are N-(2-(7-Methoxy-1-naphthalenyl)ethyl)acetamide ; N-(2-(7-Methoxy-1-naphthyl)ethyl)acetamide ; N-(2-(7-Methoxynaphth-1-yl)ethyl)acetamide ; S20098 ; Thymanax ; UNII-137R1N49AD ; Valdoxan ; Acetamide, N-(2-(7-methoxy-1-naphthalenyl)ethyl)- .

4.2 Toxicity

Organism	Test Type	Route	Reported Dose (Normalized Dose)	Effect	Source
mouse	LD50	oral	> 1gm/kg (1000mg/kg)	?	United States Patent Document. Vol. #5318994,

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5. MSDS

2.Hazard identification

2.1 Classification of the substance or mixture

Hazardous to the aquatic environment, short-term (Acute) - Category Acute 1

2.2 GHS label elements, including precautionary statements

Pictogram(s)
Signal word	Warning
Hazard statement(s)	H400 Very toxic to aquatic life
Precautionary statement(s)
Prevention	P273 Avoid release to the environment.
Response	P391 Collect spillage.
Storage	none
Disposal	P501 Dispose of contents/container to ...

2.3 Other hazards which do not result in classification

none

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6. Synthesis Route

138112-76-2Total: 59 Synthesis Route

135-19-3 328 Suppliers

138112-76-2 384 Suppliers

Literatures:
EP2562151 A1, ;
Yield: null

118-46-7 74 Suppliers

138112-76-2 384 Suppliers

Literatures:
Tetrahedron Letters, , vol. 53, # 52 p. 7125 - 7127
Yield: null

6836-20-0 1 Suppliers

138112-76-2 384 Suppliers

Literatures:
WO2014/1939 A1, ;
Yield: null

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7. Precursor and Product

precursor:

99416-99-6

6836-23-3

6836-22-2

22009-38-7

66240-21-9

118-46-7

6836-21-1

6836-20-0

63319-95-9

296280-78-9

127299-26-7

59081-66-2

59081-65-1

185336-04-3

29921-51-5

138113-09-4

27532-26-9

58150-14-4

99417-10-4

1523-11-1

158365-55-0

135-19-3

93624-01-2

158365-54-9

6836-19-7

View all

product :

152302-45-9

686319-38-0

8. Other Information

8.0 Merck: 14,190

8.1 Antidepressants: Agomelatine, which is developed by the French Servier company, is the world's first melatonin receptors MT1 and MT2 agonist class of antidepressants. It applies to the treatment of adult patients with severe depressive. We know that melatonin is an endogenous neural hormones. It is only produced by the pineal gland anterior pituitary at night, and acts on the melatonin receptor that focuses on the presence of hypothalamic suprachiasmatic nucleus (SCN). It is involved in mediating the circadian rhythms in mammals. It is the well-known time guardian in the body, which can regulate the biological clock that is modulated by external circadian cycle. However, since that melatonin has high catabolism rate in vivo which mikes its half-life shorter and the selectivity of its receptor located in the SCN poorer, the treatment of circadian rhythms disorders is limited. Therefore, in order to overcome these drawbacks of melatonin, the researchers designed a series of melatonin analogues. Molecular modeling studies have shown that indole ring of melatonin is the structure sites of catabolic inactivation. Indole ring is an ideal site of isosteric modifications. Agomelatine developed by Servier company is melatonin’s naphthalene biological (electronic) isostere analogs. Indole ring is substituted by naphthalene nucleus, which leads it have more metabolic stability than melatonin.; View all

8.2 Health risk: October 30, 2012, the British Medicines and Healthcare Products Agency (MHRA) released agomelatine (agomelatine, Valdoxan/Thymanax) security information. MHRA found that several cases appears serious reports of liver toxicity with agomelatine, including six cases of liver failure patients within worldwide report. Agomelatine's drug information already includes in the recommendations that all patients need liver function tests at the start of treatment and during treatment. Now liver function tests should also be recommended when the drug dose is increased. MHRA recommends that if the patients have potential liver damage symptoms or signs, or that the increases of serum transaminase beyond the upper limit of normal (ULN) three times is found in the function tests, it should be immediately suspended.

8.3 Patent cases: The earliest agomelatine compound patent is French Patent FR902393, which is applied in February 27, 1990. This patent has the same patent family in Europe, USA, Canada, Japan and Australia. But there is no Chinese patent. The above patents were all authorized after January 1, 1993. Therefore China is also ineligible for administrative protection. Agomelatine has both technology patent and polymorph patent in China. But it also can be avoided.

8.4 Uses: Melatonin drugs.

8.5 Chemical Properties: White Solid

8.6 Uses: Agomelatine is an antidepressant drug. It is classified as a norepinephrine-dopamine disinhibitor (NDDI) due to its antagonism of the 5-HT2C receptor. Activation of 5-HT2C receptors by serotonin inhibits dopamine and norepinephrine release. Antagonism of

8.7 Uses: Agomelatine is a melatoninergic agonist and selective antagonist of 5-HT2C receptors, and has been shown to be active in several animal models of depression. Agomelatine (S20098) displayed pKi values of 6.4 and 6.2 at native (porcine) and cloned, human (h)5-hydroxytryptamine (5-HT)2C receptors, respectively.

8.8 Collision Cross Section: 156.3 ?2 [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]

8.9 Mesh: Drugs used to induce drowsiness or sleep or to reduce psychological excitement or anxiety. (See all compounds classified as Hypnotics and Sedatives.)

8.10 Absorption: Bioavailability is less than 5%.

8.11 Metabolism: Hepatic (90% CYP1A2 and 10% CYP2C9).

8.12 Biological Half Life: <2 hours

8.13 Mesh Entry Terms: AGO 178

8.14 Use Classification: Human drugs -> Thymanax -> EMA Drug Category|Psychoanaleptics -> Human pharmacotherapeutic group|Human drugs -> Valdoxan -> EMA Drug Category|Human Drugs -> EU pediatric investigation plans

8.15 Target: Value

8.16 Description: Agomelatine is an agonist of melatonin (MT) receptors and a derivative of melatonin (Item No. 14427). It binds to MT₁ and MT₂ receptors (K_is = 0.14 and 0.41 nM, respectively) and has an EC₅₀ value of 0.1 nM in a [³⁵S]GTPγS binding assay using CHO cells expressing MT₂ receptors. Agomelatine is also an antagonist of the serotonin (5-HT) receptor subtypes 5-HT_2B and 5-HT_2C (K_is = 0.26 and 0.71 nM, respectively, for the human receptors). Agomelatine (40 mg/kg) inhibits the penile erection response induced by the 5-HT₂ agonist Ro 60-0175 (Item No. 29500) in rats. It also increases extracellular levels of noradrenaline and dopamine in the frontal cortex of freely moving rats when administered at doses ranging from 20 to 80 mg/kg. Agomelatine (10 mg/kg) reduces immobility time in the forced swim test and increases the amount of time spent in the open arms of the elevated plus maze in mice, indicating antidepressant-like and anxiolytic-like activity, in a transgenic neuroendocrine model of depression. It also increases the rate of readjustment to circadian activity cycles following an induced phase shift.; View all

8.17 Uses

Agomelatine has been used:

to study its effects on adult neurogenesis and hippocampus apoptosis using the stress-induced depression model of rats
to explore its effects on tau protein phosphorylation and to study its neuroprotective mechanism
to study its effects on intracellular calcium ([Ca²⁺]i) signaling in peripheral neurons of rat dorsal root ganglion (DRG) neurons

9. Computational chemical data

Molecular Weight: 243.306g/mol
Molecular Formula: C₁₅H₁₇NO₂
Compound Is Canonicalized: True
XLogP3-AA: 2.7
Exact Mass: 243.125928785
Monoisotopic Mass: 243.125928785
Complexity: 280
Rotatable Bond Count: 4
Hydrogen Bond Donor Count: 1
Hydrogen Bond Acceptor Count: 2
Topological Polar Surface Area: 38.3
Heavy Atom Count: 18
Defined Atom Stereocenter Count: 0
Undefined Atom Stereocenter Count: 0
Defined Bond Stereocenter Count: 0
Undefined Bond Stereocenter Count: 0
Isotope Atom Count: 0
Covalently-Bonded Unit Count: 1
CACTVS Substructure Key Fingerprint: AAADceByMAAAAAAAAAAAAAAAAAAAAAAAAAAwYAAAAAAAAADBUAAAHgAQAAAADATBmAYyBsLABACIAiFSEAACCAAgIAAIiIAOCIgMJiKEsRuEMCAk1hGIqAeQwPAOoAADAAAQAABAAAYAACAAAAAAAAAAAA==

10. Question & Answer

Can AGOMELATINE be used for the treatment of depression? Aug 08 2022
Depression can be caused by genetic factors or environmental conditions. Excessive stress can also lead to the occurrence of depression. It is important to promptly treat depression with medication. L..

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