Find Belvig manufacturers, exporters & distributors on PharmaCompass

Belvig

Belvig

Synopsis, Chemistry

APIs // Active Pharmaceutical Ingredients

1 API Suppliers, 1 Listed Suppliers

Product Search

API SUPPLIERS

API Suppliers

US DMFs Filed

CEP/COS Certifications

JDMFs Filed

Other Certificates

Other Suppliers

API REF. PRICE (USD / KG)

API Market Place

INTERMEDIATES

DOSSIERS // FDF

USA (Orange Book)

Europe

Canada

Australia

South Africa

Uploaded Dossiers

GLOBAL SALES (USD Million)

U.S. Medicaid

Annual Reports

FDF Market Place

EXCIPIENTS

PATENTS & EXCLUSIVITIES

USFDA Orange Book Patents

USFDA Exclusivities

DIGITAL CONTENT

Blog #PharmaFlow

News

REF STANDARD

EDQM

USP

Other Listed Suppliers

SERVICES

Also known as: 616202-92-7, (r)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1h-benzo[d]azepine, Belviq, (1r)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1h-3-benzazepine, Lorcaserin [inn], 1h-3-benzazepine, 8-chloro-2,3,4,5-tetrahydro-1-methyl-, (1r)-

Molecular Formula

C₁₁H₁₄ClN

Molecular Weight

195.69 g/mol

InChI Key

XTTZERNUQAFMOF-QMMMGPOBSA-N

FDA UNII

637E494O0Z

Lorcaserin (previously APD-356), a highly selective 5HT2C receptor agonist, is used for the treatment of obesity. It has been shown to reduce body weight and food intake in animal models of obesity, and it is thought that targeting the 5HT2C receptor may alter body weight by regulating satiety. Lorcaserin is marketed as a salt form called Belviq, which is lorcaserin hydrochloride.

Lorcaserin is a Serotonin-2c Receptor Agonist. The mechanism of action of lorcaserin is as a Serotonin 2c Receptor Agonist, and Cytochrome P450 2D6 Inhibitor.

1 2D Structure

Belvig

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

(5R)-7-chloro-5-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

2.1.2 InChI

InChI=1S/C11H14ClN/c1-8-7-13-5-4-9-2-3-10(12)6-11(8)9/h2-3,6,8,13H,4-5,7H2,1H3/t8-/m0/s1

2.1.3 InChI Key

XTTZERNUQAFMOF-QMMMGPOBSA-N

2.1.4 Canonical SMILES

CC1CNCCC2=C1C=C(C=C2)Cl

2.1.5 Isomeric SMILES

C[C@H]1CNCCC2=C1C=C(C=C2)Cl

2.2 Other Identifiers

2.2.1 UNII

637E494O0Z

2.3 Synonyms

2.3.1 MeSH Synonyms

1. (1r)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1h-3-benzazepine

2. 8-chloro-2,3,4,5-tetrahydro-1-methyl-1h-3-benzazepine

3. Apd 356

4. Apd-356

5. Apd356

6. Ar-10a

7. Belviq

2.3.2 Depositor-Supplied Synonyms

1. 616202-92-7

2. (r)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1h-benzo[d]azepine

3. Belviq

4. (1r)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1h-3-benzazepine

5. Lorcaserin [inn]

6. 1h-3-benzazepine, 8-chloro-2,3,4,5-tetrahydro-1-methyl-, (1r)-

7. (r)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1h-3-benzazepine

8. Chembl360328

9. Chebi:65353

10. 637e494o0z

11. Ncgc00182550-01

12. Ar-10a

13. Dsstox_cid_28585

14. Dsstox_rid_82856

15. Dsstox_gsid_48659

16. Belvig

17. Cas-616202-92-7

18. Unii-637e494o0z

19. Hsdb 8128

20. T4u

21. Lorcaserin [mi]

22. (1r)-8-chloro-2,3,4,5-tetrahydro-1-methyl-1h-3-benzazepine

23. Lorcaserin [vandf]

24. Lorcaserin [who-dd]

25. Schembl169382

26. Gtpl2941

27. Dtxsid3048659

28. 8-chloro-2,3,4,5-tetrahydro-1-methyl-1h-3-benzazepine

29. (5r)-7-chloro-5-methyl-2,3,4,5-tetrahydro-1h-3-benzazepine

30. Zinc6733300

31. Tox21_113018

32. Ac-553

33. Bdbm50161646

34. Akos006326204

35. Tox21_113018_1

36. Am81248

37. Cs-1232

38. Db04871

39. Ncgc00182550-02

40. Hy-11093

41. 202l927

42. Q340139

2.4 Create Date

2006-10-26

3 Chemical and Physical Properties

Molecular Formula	C₁₁H₁₄ClN
Molecular Weight	195.69 g/mol
XLogP3	2.7
Hydrogen Bond Donor Count	1
Hydrogen Bond Acceptor Count	1
Rotatable Bond Count	0
Exact Mass	195.0814771 g/mol
Monoisotopic Mass	195.0814771 g/mol
Topological Polar Surface Area	12 Å²
Heavy Atom Count	13
Formal Charge	0
Complexity	172
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 Drug Information

1 of 1
Drug Name	BELVIQ
Active Ingredient	LORCASERIN HYDROCHLORIDE
Company	EISAI INC (Application Number: N022529. Patents: 6953787, 7514422, 7977329, 8168624, 8207158, 8273734, 8367657, 8546379, 8575149, 8697686, 8946207, 8980881, 8999970, 9169213, 9770455)

4.2 Therapeutic Uses

Belviq is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adult patients with an initial body mass index (BMI) of: 30 kg/sq m or greater (obese), or 27 kg/sq m or greater (overweight) in the presence of at least one weight related comorbid condition (e.g., hypertension, dyslipidemia, type 2 diabetes). /Included in US product label/

US Natl Inst Health; DailyMed. Current Medication Information for BELVIQ (lorcaserin hydrochloride) tablets (August 2012). Available from, as of March 13, 2013: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=7cbbb12f-760d-487d-b789-ae2d52a3e01f

4.3 Drug Warning

Belviq is a serotonergic drug. The development of a potentially life-threatening serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions have been reported during use of serotonergic drugs, including, but not limited to, selective serotonin-norepinephrine reuptake inhibitors (SNRIs) and selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), bupropion, triptans, dietary supplements such as St. John's Wort and tryptophan, drugs that impair metabolism of serotonin (including monoamine oxidase inhibitors (MAOIs)), dextromethorphan, lithium, tramadol, antipsychotics or other dopamine antagonists, particularly when used in combination. Serotonin syndrome symptoms 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 gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Patients should be monitored for the emergence of serotonin syndrome or NMS-like signs and symptoms.

Regurgitant cardiac valvular disease, primarily affecting the mitral and/or aortic valves, has been reported in patients who took serotonergic drugs with 5-HT2B receptor agonist activity. The etiology of the regurgitant valvular disease is thought to be activation of 5-HT2B receptors on cardiac interstitial cells. At therapeutic concentrations, Belviq is selective for 5-HT2C receptors as compared to 5-HT2B receptors. In clinical trials of 1-year duration, 2.4% of patients receiving Belviq and 2.0% of patients receiving placebo developed echocardiographic criteria for valvular regurgitation at one year (mild or greater aortic regurgitation and/or moderate or greater mitral regurgitation): none of these patients was symptomatic.

Belviq is contraindicated during pregnancy, because weight loss offers no potential benefit to a pregnant woman and may result in fetal harm. Maternal exposure to lorcaserin in late pregnancy in rats resulted in lower body weight in offspring which persisted to adulthood. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard of maternal weight loss to the fetus.

Patients who develop signs or symptoms of valvular heart disease, including dyspnea, dependent edema, congestive heart failure, or a new cardiac murmur while being treated with Belviq should be evaluated and discontinuation of Belviq should be considered.

For more Drug Warnings (Complete) data for Lorcaserin (22 total), please visit the HSDB record page.

4.4 Drug Indication

For the treatment of obesity, as an adjunct to a reduced-calorie diet and increased physical activity.

FDA Label

Treatment of obesity

5 Pharmacology and Biochemistry

5.1 Pharmacology

Lorcaserin produced a dose-dependent weight loss over a 12-week period by promoting satiety and decreasing food consumption.

5.2 FDA Pharmacological Classification

5.2.1 Active Moiety

LORCASERIN

5.2.2 FDA UNII

637E494O0Z

5.2.3 Pharmacological Classes

Mechanisms of Action [MoA] - Cytochrome P450 2D6 Inhibitors

5.3 ATC Code

A - Alimentary tract and metabolism

A08 - Antiobesity preparations, excl. diet products

A08A - Antiobesity preparations, excl. diet products

A08AA - Centrally acting antiobesity products

A08AA11 - Lorcaserin

5.4 Absorption, Distribution and Excretion

Absorption

Lorcaserin has a peak plasma concentration of about 1.5 - 2 hours, but the bioavailability was not determined.

Route of Elimination

Lorcaserin is eliminated by hepatic metabolism, and the metabolites are eliminated mostly in the urine (92.3%) and some through feces (2.2%).

Volume of Distribution

The volume of distribution was not determined, but lorcaserin distributes to the central nervous system and cerebrospinal fluid.

Clearance

The clearance value was not determined.

Lorcaserin distributes to the cerebrospinal fluid and central nervous system in humans. Lorcaserin hydrochloride is moderately bound (approximately 70%) to human plasma proteins.

Lorcaserin is absorbed from the gastrointestinal tract with peak plasma concentration occurring 1.5 - 2 hours after oral dosing. The absolute bioavailability of lorcaserin has not been determined. Lorcaserin has a plasma half life of approximately 11 hours; steady state is reached within 3 days after twice daily dosing, and accumulation is estimated to be approximately 70%.

Lorcaserin is extensively metabolized by the liver and the metabolites are excreted in the urine. In a human mass balance study in which healthy subjects ingested radiolabeled lorcaserin, 94.5% of radiolabeled material was recovered, with 92.3% and 2.2% recovered from urine and feces, respectively.

5.5 Metabolism/Metabolites

Lorcaserin has extensive hepatic metabolism producing inactive compounds. Lorcaserin sulfamate (M1) is the major metabolite circulating in the plasma, and N-carbamoyl glucuronide lorcaserin (M5) is the major metabolite in urine. Other minor metabolites that are both excreted in urine are glucuronide or sulfate conjugates.

Lorcaserin is extensively metabolized in the liver by multiple enzymatic pathways. After oral administration of Belviq, the major circulating metabolite is lorcaserin sulfamate (M1), with a plasma Cmax that exceeds lorcaserin Cmax by 1- to 5-fold. N-carbamoyl glucuronide lorcaserin (M5) is the major metabolite in urine; M1 is a minor metabolite in urine, representing approximately 3% of dose. Other minor metabolites excreted in urine were identified as glucuronide or sulfate conjugates of oxidative metabolites. The principal metabolites exert no pharmacological activity at serotonin receptors.

Lorcaserin, a selective serotonin 5-hydroxytryptamine 2C receptor agonist, is being developed for weight management. The oxidative metabolism of lorcaserin, mediated by recombinant human cytochrome P450 (P450) and flavin-containing monooxygenase (FMO) enzymes, was examined in vitro to identify the enzymes involved in the generation of its primary oxidative metabolites, N-hydroxylorcaserin, 7-hydroxylorcaserin, 5-hydroxylorcaserin, and 1-hydroxylorcaserin. Human CYP1A2, CYP2A6, CYP2B6, CYP2C19, CYP2D6, CYP3A4, and FMO1 are major enzymes involved in N-hydroxylorcaserin; CYP2D6 and CYP3A4 are enzymes involved in 7-hydroxylorcaserin; CYP1A1, CYP1A2, CYP2D6, and CYP3A4 are enzymes involved in 5-hydroxylorcaserin; and CYP3A4 is an enzyme involved in 1-hydroxylorcaserin formation. In 16 individual human liver microsomal preparations (HLM), formation of N-hydroxylorcaserin was correlated with CYP2B6, 7-hydroxylorcaserin was correlated with CYP2D6, 5-hydroxylorcaserin was correlated with CYP1A2 and CYP3A4, and 1-hydroxylorcaserin was correlated with CYP3A4 activity at 10.0 uM lorcaserin. No correlation was observed for N-hydroxylorcaserin with any P450 marker substrate activity at 1.0 uM lorcaserin. N-Hydroxylorcaserin formation was not inhibited by CYP1A2, CYP2A6, CYP2B6, CYP2C19, CYP2D6, and CYP3A4 inhibitors at the highest concentration tested. Furafylline, quinidine, and ketoconazole, selective inhibitors of CYP1A2, CYP2D6, and CYP3A4, respectively, inhibited 5-hydroxylorcaserin (IC(50) = 1.914 uM), 7-hydroxylorcaserin (IC(50) = 0.213 uM), and 1-hydroxylorcaserin formation (IC(50) = 0.281 uM), respectively. N-Hydroxylorcaserin showed low and high K(m) components in HLM and 7-hydroxylorcaserin showed lower K(m) than 5-hydroxylorcaserin and 1-hydroxylorcaserin in HLM. The highest intrinsic clearance was observed for N-hydroxylorcaserin, followed by 7-hydroxylorcaserin, 5-hydroxylorcaserin, and 1-hydroxylorcaserin in HLM. Multiple human P450 and FMO enzymes catalyze the formation of four primary oxidative metabolites of lorcaserin, suggesting that lorcaserin has a low probability of drug-drug interactions by concomitant medications.

PMID:22266842 Usmani KA et al; Drug Metab Dispos 40 (4): 761-71 (2012)

Lorcaserin, a selective serotonin 5-HT(2C) receptor agonist, is a weight management agent in clinical development. Lorcaserin N-carbamoyl glucuronidation governs the predominant excretory pathway of lorcaserin in humans. Human UDP-glucuronosyltransferases (UGTs) responsible for lorcaserin N-carbamoyl glucuronidation are identified herein. Lorcaserin N-carbamoyl glucuronide formation was characterized by the following approaches: metabolic screening using human tissues (liver, kidney, intestine, and lung) and recombinant enzymes, kinetic analyses, and inhibition studies. Whereas microsomes from all human tissues studied herein were found to be catalytically active for lorcaserin N-carbamoyl glucuronidation, liver microsomes were the most efficient. With recombinant UGT enzymes, lorcaserin N-carbamoyl glucuronidation was predominantly catalyzed by three UGT2Bs (UGT2B7, UGT2B15, and UGT2B17), whereas two UGT1As (UGT1A6 and UGT1A9) played a minor role. UGT2B15 was most efficient, with an apparent K(m) value of 51.6 + or - 1.9 uM and V(max) value of 237.4 + or - 2.8 pmol/mg protein/min. The rank order of catalytic efficiency of human UGT enzymes for lorcaserin N-carbamoyl glucuronidation was UGT2B15 > UGT2B7 > UGT2B17 > UGT1A9 > UGT1A6. Inhibition of lorcaserin N-carbamoyl glucuronidation activities of UGT2B7, UGT2B15, and UGT2B17 in human liver microsomes by mefenamic acid, bisphenol A, and eugenol further substantiated the involvement of these UGT2B isoforms. In conclusion, multiple human UGT enzymes catalyze N-carbamoyl glucuronidation of lorcaserin; therefore, it is unlikely that inhibition of any one of these UGT activities will lead to significant inhibition of the lorcaserin N-carbamoyl glucuronidation pathway. Thus, the potential for drug-drug interaction by concomitant administration of a drug(s) that is metabolized by any of these UGTs is remote.

PMID:22259019 Sadeque AJ et al; Drug Metab Dispos 40 (4): 772-8 (2012)

5.6 Biological Half-Life

The plasma half life is approximately 11 hours.

5.7 Mechanism of Action

Although the exact mechanism is unknown, it is believed to involve the selective activation of 5-HT2C receptors in the anorexigenic pro-opiomelanocortin neurons in the arcuate nucleus of the hypothalamus. This results in decreased food intake and satiety by promoting the release of alpha-melanocortin stimulating hormone, which acts on melanocortin-4 receptors.

Lorcaserin is believed to decrease food consumption and promote satiety by selectively activating 5-HT2C receptors on anorexigenic pro-opiomelanocortin neurons located in the hypothalamus. The exact mechanism of action is not known.

In this study, /the researchers/ describe the in vitro and in vivo characteristics of lorcaserin ((1R)-8-chloro-2,3,4,5-tetrahydro-1-methyl-1H-3 benzazepine), a selective, high affinity 5-HT(2C) full agonist. Lorcaserin bound to human and rat 5-HT(2C) receptors with high affinity (K(i) = 15 +/- 1 nM, 29 +/- 7 nM, respectively), and it was a full agonist for the human 5-HT(2C) receptor in a functional inositol phosphate accumulation assay, with 18- and 104-fold selectivity over 5-HT(2A) and 5-HT(2B) receptors, respectively. Lorcaserin was also highly selective for human 5-HT(2C) over other human 5-HT receptors (5-HT(1A), 5-HT(3), 5-HT(4C), 5-HT5(5A), 5-HT(6), and 5-HT(7)), in addition to a panel of 67 other G protein-coupled receptors and ion channels. Lorcaserin did not compete for binding of ligands to serotonin, dopamine, and norepinephrine transporters, and it did not alter their function in vitro. Behavioral observations indicated that unlike the 5-HT(2A) agonist (+/-)-1-(2,5-dimethoxy-4-phenyl)-2-aminopropane, lorcaserin did not induce behavioral changes indicative of functional 5-HT(2A) agonist activity. Acutely, lorcaserin reduced food intake in rats, an effect that was reversed by pretreatment with the 5-HT(2C)-selective antagonist 6-chloro-5-methyl-1-[6-(2-methylpyridin-3-yloxy)pyridin-3-yl-carbamoyl]indoline (SB242,084) but not the 5-HT(2A) antagonist (R)-(+)-alpha-(2,3-dimethoxyphenyl)-1-(2-(4-fluorophenylethyl))-4-piperidine-methanol (MDL 100,907), demonstrating mediation by the 5-HT(2C) receptor. Chronic daily treatment with lorcaserin to rats maintained on a high fat diet produced dose-dependent reductions in food intake and body weight gain that were maintained during the 4-week study. Upon discontinuation, body weight returned to control levels. These data demonstrate lorcaserin to be a potent, selective, and efficacious agonist of the 5-HT(2C) receptor, with potential for the treatment of obesity.

PMID:18252809 Thomsen WJ et al; J Pharmacol Exp Ther. 2008 May;325(2):577-87 (2008)