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DOFETILIDE

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ChemSpider 2D Image | Dofetilide | C19H27N3O5S2

Dofetilide

115256-11-6[RN]

6756

b-((p-Methanesulfonamidophenethyl)methylamino)methanesulfono-p-phenetidide
Methanesulfonamide, N-[4-[2-[methyl[2-[4-[(methylsulfonyl)amino]phenoxy]ethyl]amino]ethyl]phenyl]-

MFCD00869707 [MDL number]

  • Molecular FormulaC19H27N3O5S2
  • Average mass441.565 Da
  • UK68798UNII:R4Z9X1N2NDUNII-R4Z9X1N2NDXelideβ-((p-Methanesulfonamidophenethyl)methylamino)methanesulfono-p-phenetidideдофетилидدوفيتيليد多非利特

N-[4-[2-[methyl[2-[4-[(methylsulfonyl)amino]phenoxy]ethyl]amino]ethyl]phenyl]-methanesulfonamideNCGC00164549-01PB0478000SMR000466333Tikosyn (TN)Research Code:UK-68798Trade Name:Tikosyn®MOA:Atrial potassium channel blockerIndication:Atrial flutter; Atrial fibrillationStatus:ApprovedCompany:Pfizer (Originator)Sales:ATC Code:C01BD04

INDIA 31/7/2020 APPROVED CDSCO

Dofetilide was first approved by the U.S. Food and Drug Administration (FDA) on Oct 1, 1999, then approved by European Medicine Agency (EMA) on Nov 29, 1999. It was developed and marketed as Tikosyn® by Pfizer.

Dofetilide is a selective blocker of delayed rectifier outward potassium current (IKr). It is indicated for the maintenance of normal sinus rhythm (delay in time to recurrence of atrial fibrillation/atrial flutter [AF/AFl]) in patients with atrial fibrillation/atrial flutter of greater than one week duration who have been converted to normal sinus rhythm.

Tikosyn® is available capsule for oral use, containing 0.125, 0.25 or 0.5 mg of free Dofetilide. The recommended dose is 500 µg orally twice daily.

Dofetilide is a class III antiarrhythmic agent.[1] It is marketed under the trade name Tikosyn by Pfizer, and is available in the United States in capsules containing 125, 250, and 500 µg of dofetilide. It is not available in Europe[2] or Australia.[3] In the United States it is only available by mail order or through specially trained local pharmacies.[4]

Medical uses

Dofetilide is used for the maintenance of sinus rhythm in individuals prone to the occurrence of atrial fibrillation and flutter arrhythmias, and for chemical cardioversion to sinus rhythm from atrial fibrillation and flutter.[5][6]

Based on the results of the Danish Investigations of Arrhythmias and Mortality on Dofetilide (“DIAMOND”) study,[7] dofetilide does not affect mortality in the treatment of patients post-myocardial infarction with left ventricular dysfunction, however it was shown to decrease all-cause readmissions as well as CHF-related readmissions.[8] Because of the results of the DIAMOND study, some physicians use dofetilide in the suppression of atrial fibrillation in individuals with LV dysfunction, however use appears limited: After initially receiving marketing approval in Europe in 1999, Pfizer voluntarily withdrew this approval in 2004 for commercial reasons[2] and it is not registered in other first world countries.

It has clinical advantages over other class III antiarrhythmics in chemical cardioversion of atrial fibrillation, and maintenance of sinus rhythm, and does not have the pulmonary or hepatotoxicity of amiodarone, however atrial fibrillation is not generally considered life-threatening, and dofetilide causes an increased rate of potentially life-threatening arrhythmias in comparison to other therapies.[9]

Contraindications

Prior to administration of the first dose, the corrected QT (QTc) must be determined. If the QTc is greater than 440 msec (or 500 msec in patients with ventricular conduction abnormalities), dofetilide is contraindicated. If heart rate is less than 60 bpm, the uncorrected QT interval should be used. After each subsequent dose of dofetilide, QTc should be determined and dosing should be adjusted. If at any time after the second dose of dofetilide the QTc is greater than 500 msec (550 msec in patients with ventricular conduction abnormalities), dofetilide should be discontinued. [4]

Adverse effects

Torsades de pointes is the most serious side effect of dofetilide therapy. The incidence of torsades de pointes is 0.3-10.5% and is dose-related, with increased incidence associated with higher doses. The majority of episodes of torsades de pointes have occurred within the first three days of initial dosing. Patients should be hospitalized and monitored for the first three days after starting dofetilide.[10]

The risk of inducing torsades de pointes can be decreased by taking precautions when initiating therapy, such as hospitalizing individuals for a minimum of three days for serial creatinine measurement, continuous telemetry monitoring and availability of cardiac resuscitation.

Pharmacology

Mechanism of action

Dofetilide works by selectively blocking the rapid component of the delayed rectifier outward potassium current (IKr).[11]

This causes the refractory period of atrial tissue to increase, hence its effectiveness in the treatment of atrial fibrillation and atrial flutter.

Dofetilide does not affect dV/dTmax (the slope of the upstroke of phase 0 depolarization), conduction velocity, or the resting membrane potential.

Dofetilide synthesis

There is a dose-dependent increase in the QT interval and the corrected QT interval (QTc). Because of this, many practitioners will initiate dofetilide therapy only on individuals under telemetry monitoring or if serial EKG measurements of QT and QTc can be performed.

Pharmacokinetics

Peak plasma concentrations are seen two to three hours after oral dosing when fasting. Dofetilide is well absorbed in its oral form, with a bioavailability of >90%. Intravenous administration of dofetilide is not available in the United States. [12]

The elimination half-life of dofetilide is roughly 10 hours; however, this varies based on many physiologic factors (most significantly creatinine clearance), and ranges from 4.8 to 13.5 hours. Due to the significant level of renal elimination (80% unchanged, 20% metabolites), the dose of dofetilide must be adjusted to prevent toxicity due to impaired renal function.[13]

Dofetilide is metabolized predominantly by CYP3A4 enzymes predominantly in the liver and GI tract. This means that it is likely to interact with drugs that inhibit CYP3A4, such as erythromycinclarithromycin, or ketoconazole, resulting in higher and potentially toxic levels of dofetilide. [14]

Metabolism

A steady-state plasma level of dofetilide is achieved in 2–3 days.

80% of dofetilide is excreted by the kidneys, so the dose of dofetilide should be adjusted in individuals with chronic kidney disease, based on creatinine clearance.

In the kidneys, dofetilide is eliminated via cation exchange (secretion). Agents that interfere with the renal cation exchange system, such as verapamilcimetidinehydrochlorothiazideitraconazoleketoconazoleprochlorperazine, and trimethoprim should not be administered to individuals taking dofetilide.

About 20 percent of dofetilide is metabolized in the liver via the CYP3A4 isoenzyme of the cytochrome P450 enzyme system. Drugs that interfere with the activity of the CYP3A4 isoenzyme can increase serum dofetilide levels. If the renal cation exchange system is interfered with (as with the medications listed above), a larger percentage of dofetilide is cleared via the CYP3A4 isoenzyme system.

History

After its initial US FDA approval, due to the pro-arrhythmic potential it was only made available to hospitals and prescribers that had received education and undergone specific training in the risks of treatment with dofetilide; however, this restriction was subsequently removed in 2016. [15

SYN

File:Dofetilide synthesis.png - Wikimedia Commons
File:Dofetilide synthesis.svg - Wikimedia Commons

REF

Route 1

Reference:1. US5079248A / US4959366A.

2. J. Med. Chem. 199033, 1151-1155.

str1

SYN

Thieme Pharmaceutical Substances

SYN

Solved: In The Total Synthesis Of Dofetilid Step (f) Was S... | Chegg.com

SYN

Step 1
Step 2

SYN

EP 0245997; JP 1987267250; US 4959366; US 5079248

This compound can be prepared by several related ways: 1) The condensation of N-methyl-2-(4-nitrophenyl)ethylamine (I) with 4-(2-chloroethoxy)nitrobenzene (II) by means of NaI and K2CO3 in refluxing acetonitrile gives 1-(4-nitrophenoxy)-5-(4-nitrophenyl)-3-methyl-3-azapentane (III), which is reduced with H2 over Pd/C in ethanol, yielding the corresponding diamino derivative (IV). Finally, this compound is acylated with methanesulfonyl anhydride in dichloromethane. 2) The condensation of (I) with N-[4-(2-chloroethoxy)phenyl]methanesulfonamide (V) with NaI and K2CO3 as before gives 1-[4-(methanesulfonamide)phenoxy]-3-methyl-5-(4-nitrophenyl)-3-azapentane (VI), which is reduced with H2 over Pd/C as before, yielding the corresponding amino derivative (VII). Finally, this compound is acylated with methanesulfonyl anhydride as usual. 3) The condensation of (II) with N-[4-[2-(methylamino)ethyl]phenyl]methanesulfonamide (VIII) with NaI and K2CO3 as usual gives 1-[4-(methanesulfonamido)phenyl]-3-methyl-5-(4-nitrophenoxy)-3-azapentane (IX), which is reduced with H2 and RaNi to the corresponding amino derivative (X). Finally, this compound is acylated with methanesulfonyl chloride and pyridine. 4) By condensation of N-[4-[2-(methanesulfonyloxy)ethyl]phenyl]methanesulfonamide (XI) with N-[4-[2-(methylamino)ethoxy]phenyl]methanesulfonamide (XII) in refluxing ethanol. 5) By condensation of (V) with (VIII) by means of NaHCO3.

References

  1. ^ Lenz TL; Hilleman DE (July 2000). “Dofetilide, a new class III antiarrhythmic agent”. Pharmacotherapy20 (7): 776–86. doi:10.1592/phco.20.9.776.35208PMID 10907968.
  2. Jump up to:a b Wathion, Noel (2004-04-13). “Public Statement on Tikosyn (dofetilide): Voluntary Withdrawal of the Marketing Authorisation in the European Union” (PDF). European Agency for the Evaluation of Medicinal Products.
  3. ^ Australian Medicines Handbook 2014
  4. Jump up to:a b TIKOSYN® (dofetilide). Pfizer. <http://www.tikosyn.com/>.
  5. ^ Banchs JE; Wolbrette DL; Samii SM; et al. (November 2008). “Efficacy and safety of dofetilide in patients with atrial fibrillation and atrial flutter”. J Interv Card Electrophysiol23(2): 111–5. doi:10.1007/s10840-008-9290-6PMID 18688699S2CID 25162347.
  6. ^ Lenz TL; Hilleman DE (November 2000). “Dofetilide: A new antiarrhythmic agent approved for conversion and/or maintenance of atrial fibrillation/atrial flutter”. Drugs Today36 (11): 759–71. doi:10.1358/dot.2000.36.11.601530PMID 12845335.
  7. ^ Torp-Pedersen C, Møller M, Bloch-Thomsen PE, et al. (September 1999). “Dofetilide in patients with congestive heart failure and left ventricular dysfunction. Danish Investigations of Arrhythmia and Mortality on Dofetilide Study Group”. The New England Journal of Medicine341 (12): 857–65. doi:10.1056/NEJM199909163411201PMID 10486417.
  8. ^ Torp-Pedersen C; ller M; Mø Bloch-Thomsen PE; et al. (September 1999). “Dofetilide in patients with congestive heart failure and left ventricular dysfunction. Danish Investigations of Arrhythmia and Mortality on Dofetilide Study Group”. N. Engl. J. Med341 (12): 857–65. doi:10.1056/NEJM199909163411201PMID 10486417.
  9. ^ Micromedex Drugdex drug evaluations micromedex.com
  10. ^ Torp-Pedersen C, Møller M, Bloch-Thomsen PE, et al. Dofetilide in patients with congestive heart failure and left ventricular dysfunction. Danish Investigations of Arrhythmia and Mortality on Dofetilide Study Group. N Engl J Med 1999; 341:857.
  11. ^ Roukoz H; Saliba W (January 2007). “Dofetilide: a new class III antiarrhythmic agent”. Expert Rev Cardiovasc Ther5 (1): 9–19. doi:10.1586/14779072.5.1.9PMID 17187453S2CID 11255636.
  12. ^ 1Rasmussen HS, Allen MJ, Blackburn KJ, et al. Dofetilide, a novel class III antiarrhythmic agent. J Cardiovasc Pharmacol 1992; 20 Suppl 2:S96.
  13. ^ “Dofetilide.” Lexicomp. Wulters Kluwer Health, n.d. Web. <online.lexi.com>.
  14. ^ Walker DK, Alabaster CT, Congrave GS, et al. Significance of metabolism in the disposition and action of the antidysrhythmic drug, dofetilide. In vitro studies and correlation with in vivo data. Drug Metab Dispos 1996; 24:447.
  15. ^ “Information for Tikosyn (dofetilide)”US Food and Drug Administration. 2016-03-09.

DofetilideCAS Registry Number: 115256-11-6CAS Name:N-[4-[2-[Methyl[2-[4-[(methylsulfonyl)amino]phenoxy]ethyl]amino]ethyl]phenyl]methanesulfonamideAdditional Names: 1-(4-methanesulfonamidophenoxy)-2-[N-(4-methanesulfonamidophenethyl)-N-methylamino]ethaneManufacturers’ Codes: UK-68798Trademarks: Tikosyn (Pfizer)Molecular Formula: C19H27N3O5S2Molecular Weight: 441.56Percent Composition: C 51.68%, H 6.16%, N 9.52%, O 18.12%, S 14.52%Literature References: Potassium channel blocker. Prepn: J. E. Arrowsmith et al.,EP245997; P. E. Cross et al.,US4959366 (1987, 1990 both to Pfizer); idemet al.,J. Med. Chem.33, 1151 (1990). HPLC determn in urine: D. K. Walker et al.,J. Chromatogr.568, 475 (1991). Mechanism of action study: D. Carmeliet, J. Pharmacol. Exp. Ther.262, 809 (1992). Review of pharmacology and pharmacokinetics: H. S. Rasmussen et al.,ibid.20, Suppl. 2, S96-S105 (1992). Clinical trial in atrial fibrillation and flutter: B. L. Norgaard et al.,Am. Heart J.137, 1062 (1999); in congestive heart failure: C. Torp-Pedersen et al.,N. Engl. J. Med.341, 857 (1999).Properties: Crystals from ethyl acetate/methanol (10:1), mp 147-149° (Cross); from hexane/ethyl acetate, mp 151-152° (Arrowsmith). Also reported as white crystalline solid, mp 161° (Rasmussen). pKa 7.0, 9.0, 9.6. Distribution coefficient (pH 7.4): 0.96. Sol in 0.1M NaOH, acetone, 0.1M HCl; very slightly sol in water, propan-2-ol.Melting point: mp 147-149° (Cross); mp 151-152° (Arrowsmith); mp 161° (Rasmussen)pKa: pKa 7.0, 9.0, 9.6Therap-Cat: Antiarrhythmic (class III).Keywords: Antiarrhythmic; Potassium Channel Blocker.

Clinical data
AHFS/Drugs.comMonograph
MedlinePlusa601235
ATC codeC01BD04 (WHO)
Pharmacokinetic data
Bioavailability96% (oral)
Protein binding60% -70%
Elimination half-life10 hours
Identifiers
IUPAC name[show]
CAS Number115256-11-6 
PubChem CID71329
IUPHAR/BPS2604
DrugBankDB00204 
ChemSpider64435 
UNIIR4Z9X1N2ND
KEGGD00647 
ChEBICHEBI:4681 
ChEMBLChEMBL473 
CompTox Dashboard (EPA)DTXSID5046433 
ECHA InfoCard100.166.441 
Chemical and physical data
FormulaC19H27N3O5S2
Molar mass441.56 g·mol−1
3D model (JSmol)Interactive image
SMILES[hide]O=S(=O)(Nc1ccc(cc1)CCN(CCOc2ccc(cc2)NS(=O)(=O)C)C)C
InChI[hide]InChI=1S/C19H27N3O5S2/c1-22(13-12-16-4-6-17(7-5-16)20-28(2,23)24)14-15-27-19-10-8-18(9-11-19)21-29(3,25)26/h4-11,20-21H,12-15H2,1-3H3 Key:IXTMWRCNAAVVAI-UHFFFAOYSA-N 

////////////DOFETILIDE, 2020 APPROVALS, INDIA 2020, UK 68798, UNII:R4Z9X1N2ND, дофетилид , دوفيتيليد ,多非利特 , TIKOSYN


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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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