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CAS 128196-01-0

CAS 128196-01-0

Chemistry, 2 End Use API, 39 Related Intermediates

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Also known as: 128196-01-0, (s)-citalopram, S(+)-citalopram, (+)-citalopram, Seroplex, S-(+)-citalopram

Molecular Formula

C₂₀H₂₁FN₂O

Molecular Weight

324.4 g/mol

InChI Key

WSEQXVZVJXJVFP-FQEVSTJZSA-N

FDA UNII

4O4S742ANY

S-enantiomer of CITALOPRAM. Belongs to a class of drugs known as SELECTIVE SEROTONIN REUPTAKE INHIBITORS, used to treat depression and generalized anxiety disorder.

Escitalopram is a Serotonin Reuptake Inhibitor. The mechanism of action of escitalopram is as a Serotonin Uptake Inhibitor.

1 2D Structure

CAS 128196-01-0

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

(1S)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-3H-2-benzofuran-5-carbonitrile

2.1.2 InChI

InChI=1S/C20H21FN2O/c1-23(2)11-3-10-20(17-5-7-18(21)8-6-17)19-9-4-15(13-22)12-16(19)14-24-20/h4-9,12H,3,10-11,14H2,1-2H3/t20-/m0/s1

2.1.3 InChI Key

WSEQXVZVJXJVFP-FQEVSTJZSA-N

2.1.4 Canonical SMILES

CN(C)CCCC1(C2=C(CO1)C=C(C=C2)C#N)C3=CC=C(C=C3)F

2.1.5 Isomeric SMILES

CN(C)CCC[C@@]1(C2=C(CO1)C=C(C=C2)C#N)C3=CC=C(C=C3)F

2.2 Other Identifiers

2.2.1 UNII

4O4S742ANY

2.3 Synonyms

2.3.1 MeSH Synonyms

1. Escitalopram Oxalate

2. Lexapro

2.3.2 Depositor-Supplied Synonyms

1. 128196-01-0

2. (s)-citalopram

3. S(+)-citalopram

4. (+)-citalopram

5. Seroplex

6. S-(+)-citalopram

7. Esertia

8. Cipralex

9. Escitalopram [inn]

10. Esitol

11. (1s)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile

12. Escitalopram (inn)

13. Chembl1508

14. (s)-1-(3-(dimethylamino)propyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile

15. 4o4s742any

16. Chebi:36791

17. (+)-(s)-1-(3-(dimethylamino)propyl)-1-(p-fluorophenyl)-5-phthalancarbonitrile

18. (1s)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-3h-2-benzofuran-5-carbonitrile

19. Lu-26-054

20. 5-isobenzofurancarbonitrile, 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-, (1s)-

21. 5-isobenzofurancarbonitrile, 1-(3-(dimethylamino)propyl)-1-(4-fluorophenyl)-1,3-dihydro-, (1s)-

22. Esertia (tn)

23. Escitalopram [inn:ban]

24. Escitalopramum

25. Unii-4o4s742any

26. 68p

27. Spectrum_001401

28. Tocris-1427

29. Spectrum2_000551

30. Spectrum3_001062

31. Spectrum4_001212

32. Spectrum5_001693

33. Escitalopram [mi]

34. Lopac-c-7861

35. Escitalopram [vandf]

36. Bidd:pxr0135

37. Schembl34948

38. Bspbio_002644

39. Kbiogr_001644

40. Kbioss_001881

41. Escitalopram [who-dd]

42. Spbio_000621

43. Gtpl7177

44. Dtxsid8048440

45. Hsdb 8410

46. Kbio2_001881

47. Kbio2_004449

48. Kbio2_007017

49. Kbio3_001864

50. Hms2089o08

51. Escitalopram [ep Monograph]

52. (s)-citalopram;s-(+)-citalopram

53. Bcp12154

54. Zinc3800706

55. Bdbm50302225

56. Akos017343470

57. 2-methoxyethylp-toluenesulfonate

58. Ac-1594

59. Ac-4508

60. Cs-2053

61. Db01175

62. Sb17453

63. (1r)-1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-3h-isobenzofuran-5-carbonitrile

64. (1s)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-3h-isobenzofuran-5-carbonitrile

65. Mrf-0000226

66. Ncgc00015267-01

67. Ncgc00015267-02

68. Ncgc00015267-03

69. Ncgc00015267-06

70. Ncgc00025160-01

71. Ncgc00178555-01

72. Ncgc00178555-07

73. Hy-14258

74. B1183

75. D07913

76. Ab00698374-07

77. Ab00698374-09

78. Ab00698374_10

79. A805793

80. Q423757

81. J-005570

82. Brd-k70301876-034-02-0

83. (s)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5 Carbonitrile

84. S-(+)-1-(3-(dimethylamino)propyl)-1-(p-fluorophenyl)-5-phthalancarbonitrile

85. (s)-(+)-1-[3-(dimethylamino) Propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuran Carbonitrile

86. (s)-(+)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuran Carbonitrile

87. S-(+)-5-isobenzofurancarbonitrile, 1-(3-(dimethylamino)propyl)-1-(4-fluorophenyl)-1,3-dihydro-

2.4 Create Date

2005-08-08

3 Chemical and Physical Properties

Molecular Formula	C₂₀H₂₁FN₂O
Molecular Weight	324.4 g/mol
XLogP3	3.2
Hydrogen Bond Donor Count	0
Hydrogen Bond Acceptor Count	4
Rotatable Bond Count	5
Exact Mass	g/mol
Monoisotopic Mass	g/mol
Topological Polar Surface Area	36.3
Heavy Atom Count	24
Formal Charge	0
Complexity	466
Isotope Atom Count	0
Defined Atom Stereocenter Count	1
Undefined Atom Stereocenter Count	0
Defined Bond Stereocenter Count	0
Undefined Bond Stereocenter Count	0
Covalently Bonded Unit Count	1

4 Drug and Medication Information

4.1 Therapeutic Uses

Serotonin Uptake Inhibitors; Antidepressive Agents, Second-Generation

National Library of Medicine's Medical Subject Headings. Escitalopram. Online file (MeSH, 2018). Available from, as of March 7, 2018: https://meshb.nlm.nih.gov/search

/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Escitalopram is included in the database.

NIH/NLM; ClinicalTrials.Gov. Available from, as of March 7, 2018: https://clinicaltrials.gov/

Lexapro (escitalopram) is indicated for the acute and maintenance treatment of major depressive disorder in adults and in adolescents 12 to 17 years of age. A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning, and includes at least five of the following nine symptoms: depressed mood, loss of interest in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt or suicidal ideation. /Included in US product label/

NIH; DailyMed. Current Medication Information for Lexapro (Escitalopram Oxalate) Tablet, Film Coated; Lexapro (Escitalopram Oxalate) Solution (Updated: January 26, 2017). Available from, as of March 27, 2018: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=13bb8267-1cab-43e5-acae-55a4d957630a

Lexapro is indicated for the acute treatment of Generalized Anxiety Disorder (GAD) in adult. Generalized Anxiety Disorder (DSM-IV) is characterized by excessive anxiety and worry (apprehensive expectation) that is persistent for at least 6 months and which the person finds difficult to control. It must be associated with at least 3 of the following symptoms: restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, and sleep disturbance. /Included in US product label/

For more Therapeutic Uses (Complete) data for Escitalopram (9 total), please visit the HSDB record page.

4.2 Drug Warning

/BOXED WARNING/ WARNING: Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of Lexapro or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Lexapro is not approved for use in pediatric patients less than 12 years of age.

Potentially life-threatening serotonin syndrome or neuroleptic malignant syndrome (NMS)-like reactions have been reported with selective serotonin-reuptake inhibitors (SSRIs), including escitalopram, and selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs) alone, but particularly with concurrent use of other serotonergic drugs (including serotonin (5-hydroxytryptamine; 5-HT) type 1 receptor agonists ("triptans")), drugs that impair the metabolism of serotonin (e.g., MAO inhibitors), or antipsychotics or other dopamine antagonists. Manifestations of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or GI symptoms (e.g., nausea, vomiting, diarrhea). In its most severe form, serotonin syndrome may resemble NMS, which is characterized by hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation in vital signs, and mental status changes. Patients receiving escitalopram should be monitored for the development of serotonin syndrome or NMS-like signs and symptoms.

American Society of Health-System Pharmacists 2017; Drug Information 2017. Bethesda, MD. 2017, p. 2462

The use of monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders with Lexapro or within 14 days of stopping treatment with Lexapro is contraindicated because of an increased risk of serotonin syndrome. The use of Lexapro within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated. Starting Lexapro in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome.

If concomitant use of Lexapro with other serotonergic drugs including, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, amphetamine and St. John's Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.

For more Drug Warnings (Complete) data for Escitalopram (20 total), please visit the HSDB record page.

4.3 Drug Indication

Escitalopram is indicated for both acute and maintenance treatment of major depressive disorder (MDD) and for the acute treatment of generalized anxiety disorder (GAD). It is additionally indicated for symptomatic relief of obsessive-compulsive disorder (OCD) in Canada.

5 Pharmacology and Biochemistry

5.1 MeSH Pharmacological Classification

Selective Serotonin Reuptake Inhibitors

Compounds that specifically inhibit the reuptake of serotonin in the brain. (See all compounds classified as Selective Serotonin Reuptake Inhibitors.)

5.2 ATC Code

N06AB10

S76 | LUXPHARMA | Pharmaceuticals Marketed in Luxembourg | Pharmaceuticals marketed in Luxembourg, as published by d'Gesondheetskeess (CNS, la caisse nationale de sante, www.cns.lu), mapped by name to structures using CompTox by R. Singh et al. (in prep.). List downloaded from https://cns.public.lu/en/legislations/textes-coordonnes/liste-med-comm.html. Dataset DOI:10.5281/zenodo.4587355

N - Nervous system

N06 - Psychoanaleptics

N06A - Antidepressants

N06AB - Selective serotonin reuptake inhibitors

N06AB10 - Escitalopram

5.3 Absorption, Distribution and Excretion

Absorption

Absorption of escitalopram following oral administration is expected to be almost complete, with an estimated absolute bioavailability of approximately 80%. T_max occurs after about 4-5 hours. C_max and AUC appear to follow dose proportionality - at steady state, patients receiving 10mg of escitalopram daily had a C_max of 21 ng/mL and a 24h AUC of approximately 360 ng*h/mL, while patients receiving 30mg daily had a roughly 3-fold increase in both C_max and 24h AUC, comparatively.

Route of Elimination

After oral administration of escitalopram, approximately 8% of the total dose is eliminated in the urine as unchanged escitalopram and 10% is eliminated in the urine as S-desmethylcitalopram. The apparent hepatic clearance of escitalopram amounts to approximately 90% of the total dose.

Volume of Distribution

Escitalopram appears to distribute extensively into tissues, with an apparent volume of distribution of approximately 12-26 L/kg.

Clearance

The oral plasma clearance of escitalopram is 600 mL/min, of which approximately 7% is due to renal clearance.

/MILK/ Escitalopram is excreted in human breast milk. Limited data from women taking 10-20 mg escitalopram showed that exclusively breast-fed infants receive approximately 3.9% of the maternal weight-adjusted dose of escitalopram and 1.7% of the maternal weight-adjusted dose of desmethylcitalopram.

The absolute bioavailability of citalopram is about 80% relative to an intravenous dose, and the volume of distribution of citalopram is about 12 L/kg. Data specific on escitalopram are unavailable. The binding of escitalopram to human plasma proteins is approximately 56%.

Following a single oral dose (20 mg tablet or solution) of escitalopram, peak blood levels occur at about 5 hours. Absorption of escitalopram is not affected by food.

5.4 Metabolism/Metabolites

The metabolism of escitalopram is mainly hepatic, mediated primarily by CYP2C19 and CYP3A4 and, to a lesser extent, CYP2D6. Oxidative N-demethylation by the CYP enzyme system results in S-desmethylcitalopram (S-DCT) and S-didesmethylcitalopram (S-DDCT) - these metabolites do not contribute to the pharmacologic activity of escitalopram, and exist in the plasma in small quantities relative to the parent compound (28-31% and <5%, respectively). There is also some evidence that escitalopram is metabolized to a propionic acid metabolite by monoamine oxidase A and B in the brain, and that these enzymes constitute the major route of escitalopram metabolism in the brain.

The antidepressant escitalopram is predominantly metabolized by the polymorphic CYP2C19 enzyme. The authors investigated the effect of CYP2C19 genotype on exposure and therapeutic failure of escitalopram in a large patient population. A total of 4,228 escitalopram serum concentration measurements from 2,087 CYP2C19-genotyped patients 10-30 hours after drug intake were collected retrospectively from the drug monitoring database at Diakonhjemmet Hospital in Oslo. The patients were divided into subgroups based on CYP2C19 genotype: those carrying inactive (CYP2C19Null) and gain-of-function (CYP2C19*17) variant alleles. The between-subgroup differences in escitalopram exposure (endpoint: dose-harmonized serum concentration) and therapeutic failure (endpoint: switching to another antidepressant within 1 year after the last escitalopram measurement) were evaluated by multivariate mixed model and chi-square analysis, respectively. Compared with the CYP2C19*1/*1 group, escitalopram serum concentrations were significantly increased 3.3-fold in the CYP2C19Null/Null group, 1.6-fold in the CYP2C19*Null/*1 group, and 1.4-fold in the CYP2C19Null/*17 group, whereas escitalopram serum concentrations were significantly decreased by 10% in the CYP2C19*1/*17 group and 20% in the CYP1C19*17/*17 group. In comparison to the CYP2C19*1/*1 group, switches from escitalopram to another antidepressant within 1 year were 3.3, 1.6, and 3.0 times more frequent among the CYP2C19Null/Null, CYP2C19*1/*17, and CYP1C19*17/*17 groups, respectively. The CYP2C19 genotype had a substantial impact on exposure and therapeutic failure of escitalopram, as measured by switching of antidepressant therapy. The results support the potential clinical utility of CYP2C19 genotyping for individualization of escitalopram therapy.

PMID:29325448 Jukic MM et al; Am J Psychiatry. 2018 Jan 12:appiajp201717050550. doi: 10.1176/appi.ajp.2017.17050550. (Epub ahead of print)

Escitalopram is metabolized to S-demethylcitalopram (S-DCT) and S-didemethylcitalopram (S-DDCT). In humans, unchanged escitalopram is the predominant compound in plasma. At steady state, the concentration of the escitalopram metabolite S-DCT in plasma is approximately one-third that of escitalopram. The level of S-DDCT was not detectable in most subjects. In vitro studies show that escitalopram is at least 7 and 27 times more potent than S-DCT and S-DDCT, respectively, in the inhibition of serotonin reuptake, suggesting that the metabolites of escitalopram do not contribute significantly to the antidepressant actions of escitalopram. S-DCT and S-DDCT also have no or very low affinity for serotonergic (5-HT1-7) or other receptors including alpha- and beta-adrenergic, dopamine (D1-5), histamine (H1-3), muscarinic (M1-5), and benzodiazepine receptors. S-DCT and S-DDCT also do not bind to various ion channels including Na+, K+, Cl-, and Ca++ channels. In vitro studies using human liver microsomes indicated that CYP3A4 and CYP2C19 are the primary isozymes involved in the Ndemethylation of escitalopram.

5.5 Biological Half-Life

The elimination half-life of escitalopram is 27-32 hours, though this is increased by approximately 50% in the elderly and doubled in patients with reduced hepatic function. The elimination half-life of escitalopram's primary metabolite, S-desmethylcitalopram, is approximately 54 hours at steady state.

Biotransformation of escitalopram is mainly hepatic, with a mean terminal half-life of about 27-32 hours.

5.6 Mechanism of Action

Escitalopram, like other selective serotonin re-uptake inhibitors, enhances serotonergic activity by binding to the orthosteric (i.e. primary) binding site on the serotonin transporter (SERT), the same site to which endogenous 5-HT binds, and thus prevents the re-uptake of serotonin into the presynaptic neuron. Escitalopram, along with [paroxetine], is also considered an allosteric serotonin re-uptake inhibitor - it binds to a secondary allosteric site on the SERT molecule to more strongly inhibit 5-HT re-uptake. Its combination of orthosteric and allosteric activity on SERT allows for greater extracellular 5-HT levels, a faster onset of action, and greater efficacy as compared to other SSRIs. The sustained elevation of synaptic 5-HT eventually causes desensitization of 5-HT_1A auto-receptors, which normally shut down endogenous 5-HT release in the presence of excess 5-HT - this desensitization may be necessary for the full clinical effect of SSRIs and may be responsible for their typically prolonged onset of action. Escitalopram has shown little-to-no binding affinity at a number of other receptors, such as histamine and muscarinic receptors, and minor activity at these off-targets may explain some of its adverse effects.

The mechanism of antidepressant action of escitalopram, the S-enantiomer of racemic citalopram, is presumed to be linked to potentiation of serotonergic activity in the central nervous system (CNS) resulting from its inhibition of CNS neuronal reuptake of serotonin (5-HT).