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Letermovir

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9 API Suppliers
3 USDMF
7 Listed Suppliers
$ API Reference Price

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7 Drugs in Development

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18 FDF Dossiers
8 FDA Orange Book
4 Europe
4 Canada
2 South Africa

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41 Fillers, Diluents & Binders
19 Direct Compression
14 Thickeners and Stabilizers
14 Disintegrants & Superdisintegrants
11 Lubricants & Glidants
11 Co-Processed Excipients
10 Granulation
7 Coating Systems & Additives
6 Parenteral
6 Taste Masking
5 Controlled & Modified Release
4 Film Formers & Plasticizers
3 Emulsifying Agents
3 Solubilizers
2 Coloring Agents
2 Rheology Modifiers
2 Chewable & Orodispersible Aids
1 API Stability Enhancers

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GLOBAL SALES INFORMATION

1 US Medicaid Prescriptions, 4 Finished Drug Prices, 4 Annual Reports

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1 US Medicaid Prescriptions
4 Finished Drug Prices
4 Annual Reports

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2 APIs, 1 FDF Dossiers

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2 APIs
1 FDF Dossiers

PATENTS & EXCLUSIVITIES

12 US Patents, 26 US Exclusivities

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12 US Patents
26 US Exclusivities

Lebsa Letermovir

Synopsis

ACTIVE PHARMA INGREDIENTS

API Suppliers

USDMF

CEP/COS

JDMF

EU WC

KDMF

NDC API

VMF

Listed Suppliers

API REF. PRICE (USD/KG)

$ 12,265

MARKET PLACE

API

FDF

12INTERMEDIATES

FINISHED DOSAGE FORMULATIONS

FDF Dossiers

FDA Orange Book

Europe

Canada

Australia

South Africa

Listed Dossiers

7DRUGS IN DEVELOPMENT

DRUG PRODUCT COMPOSITIONS

REF. STANDARDS OR IMPURITIES

EDQM

USP

Others

PATENTS & EXCLUSIVITIES

US Patents

US Exclusivities

Health Canada Patents

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Data Compilation #PharmaFlow

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News #PharmaBuzz

GLOBAL SALES INFORMATION

US Medicaid (USD)

48,827,212

Annual Reports (USD Million)

1,684

Finished Drug Prices

102 RELATED EXCIPIENT COMPANIES

161EXCIPIENTS BY APPLICATIONS

Chemistry

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Also known as: 917389-32-3, Aic246, Prevymis, Aic-246, Aic 246, Mk-8228

Molecular Formula

C₂₉H₂₈F₄N₄O₄

Molecular Weight

572.5 g/mol

InChI Key

FWYSMLBETOMXAG-QHCPKHFHSA-N

FDA UNII

1H09Y5WO1F

Letermovir is an orally bioavailable, non-nucleoside, 3,4-dihydroquinazolinyl acetic acid and inhibitor of the pUL56 subunit of the viral terminase complex of cytomegalovirus (CMV), with potential CMV-specific antiviral activity. Upon oral administration, letermovir binds to the pUL56 subunit of the viral terminase complex of CMV and prevents the cleavage of concatemeric DNA into monomeric genome length DNA. As this agent interferes with viral DNA processing and subsequent viral DNA packaging into procapsids, CMV replication is blocked and CMV infection is prevented.

Letermovir is a Cytomegalovirus DNA Terminase Complex Inhibitor. The mechanism of action of letermovir is as a DNA Terminase Complex Inhibitor, and Cytochrome P450 3A Inhibitor, and Organic Anion Transporting Polypeptide 1B1 Inhibitor, and Organic Anion Transporting Polypeptide 1B3 Inhibitor, and Cytochrome P450 2C8 Inhibitor, and Cytochrome P450 2C9 Inducer, and Cytochrome P450 2C19 Inducer.

1 2D Structure

Letermovir

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetic acid

2.1.2 InChI

InChI=1S/C29H28F4N4O4/c1-40-20-6-3-5-19(16-20)35-11-13-36(14-12-35)28-34-27-21(7-4-8-22(27)30)23(17-26(38)39)37(28)24-15-18(29(31,32)33)9-10-25(24)41-2/h3-10,15-16,23H,11-14,17H2,1-2H3,(H,38,39)/t23-/m0/s1

2.1.3 InChI Key

FWYSMLBETOMXAG-QHCPKHFHSA-N

2.1.4 Canonical SMILES

COC1=C(C=C(C=C1)C(F)(F)F)N2C(C3=C(C(=CC=C3)F)N=C2N4CCN(CC4)C5=CC(=CC=C5)OC)CC(=O)O

2.1.5 Isomeric SMILES

COC1=C(C=C(C=C1)C(F)(F)F)N2[C@H](C3=C(C(=CC=C3)F)N=C2N4CCN(CC4)C5=CC(=CC=C5)OC)CC(=O)O

2.2 Other Identifiers

2.2.1 UNII

1H09Y5WO1F

2.3 Synonyms

2.3.1 MeSH Synonyms

1. Aic246

2. Prevymis

2.3.2 Depositor-Supplied Synonyms

1. 917389-32-3

2. Aic246

3. Prevymis

4. Aic-246

5. Aic 246

6. Mk-8228

7. 1h09y5wo1f

8. 2-[(4s)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4h-quinazolin-4-yl]acetic Acid

9. 2-((4s)-8-fluoro-2-(4-(3-methoxyphenyl)piperazin-1-yl)-3-(2-methoxy-5-(trifluoromethyl)phenyl)-4h-quinazolin-4-yl)acetic Acid

10. 4-quinazolineacetic Acid, 8-fluoro-3,4-dihydro-2-(4-(3-methoxyphenyl)-1-piperazinyl)-3-(2-methoxy-5-(trifluoromethyl)phenyl)-, (4s)-

11. Letermovir [inn]

12. Letermovir [usan:inn]

13. Unii-1h09y5wo1f

14. Prevymis (tn)

15. (s)-[8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-(2-methoxy-5-trifluoromethylphenyl)-3,4-dihydroquinazoline-4-yl]acetic Acid

16. (s)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-(2-methoxy-5-trifluoromethylphenyl)-3,4-dihydroquinazoline-4-yl}acetic Acid

17. Mk-8828

18. Letermovir(aic246)

19. Letermovir [mi]

20. Letermovir [jan]

21. Letermovir [usan]

22. Letermovir [who-dd]

23. Letermovir (jan/usan/inn)

24. Schembl379403

25. Chembl1241951

26. Letermovir [orange Book]

27. Dtxsid40238683

28. Ex-a1871

29. S8873

30. Zinc100369359

31. Cs-1571

32. Db12070

33. Aic246;aic 246;aic-246

34. Ncgc00378936-01

35. Ncgc00378936-02

36. Ac-35698

37. As-56206

38. Hy-15233

39. J3.556.145e

40. D10801

41. D71052

42. A902281

43. Q15409407

44. (4s)-2-(8-fluoro-2-(4-(3-methoxyphenyl)piperazin-1-yl)-3-(2-methoxy-5-(trifluoromethyl)phenyl)-3,4-dihydroquinazolin-4-yl)acetic Acid

45. (4s)-8-fluoro-3,4-dihydro-2-[4-(3-methoxyphenyl)-1-piperazinyl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4-quinazolineacetic Acid

46. (s)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-(2-methoxy-5-trifluoromethylphenyl)-3,4-dihydro-quinazolin-4-yl}acetic Acid

47. (s)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-(2-methoxy-5-trifluoromethylphenyl)-3,4-dihydroquinazolin-4-yl}acetic Acid

48. (s)-2-(8-fluoro-3-(2-methoxy-5-(trifluoromethyl)phenyl)-2-(4-(3-methoxyphenyl)piperazin-1-yl)-3,4-dihydroquinazolin-4-yl)acetic Acid

2.4 Create Date

2010-04-26

3 Chemical and Physical Properties

Molecular Formula	C₂₉H₂₈F₄N₄O₄
Molecular Weight	572.5 g/mol
XLogP3	4.6
Hydrogen Bond Donor Count	1
Hydrogen Bond Acceptor Count	10
Rotatable Bond Count	7
Exact Mass	572.20466804 g/mol
Monoisotopic Mass	572.20466804 g/mol
Topological Polar Surface Area	77.8 Å²
Heavy Atom Count	41
Formal Charge	0
Complexity	931
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 Indication

For use in prophylaxis of cytomegalovirus (CMV) infection and disease in adult CMV-seropositive recipients of an allogeneic hematopoietic stem cell transplant (HSCT).

FDA Label

Prevymis is indicated for prophylaxis of cytomegalovirus (CMV) reactivation and disease in adult CMV-seropositive recipients [R+] of an allogeneic haematopoietic stem cell transplant (HSCT).

Consideration should be given to official guidance on the appropriate use of antiviral agents.

5 Pharmacology and Biochemistry

5.1 Pharmacology

Letermovir inhibits the activity of the DNA terminase complex of CMV thereby preventing the cutting of viral DNA into mature length genomes for packaging into viral particles. Letemovir inhibits the DNA terminase complex with an EC50 of 2.1nM.

5.2 MeSH Pharmacological Classification

Antiviral Agents

Agents used in the prophylaxis or therapy of VIRUS DISEASES. Some of the ways they may act include preventing viral replication by inhibiting viral DNA polymerase; binding to specific cell-surface receptors and inhibiting viral penetration or uncoating; inhibiting viral protein synthesis; or blocking late stages of virus assembly. (See all compounds classified as Antiviral Agents.)

Poly(ADP-ribose) Polymerase Inhibitors

Chemicals and drugs that inhibit the action of POLY(ADP-RIBOSE)POLYMERASES. (See all compounds classified as Poly(ADP-ribose) Polymerase Inhibitors.)

5.3 FDA Pharmacological Classification

5.3.1 Active Moiety

LETERMOVIR

5.3.2 FDA UNII

1H09Y5WO1F

5.3.3 Pharmacological Classes

Cytochrome P450 2C8 Inhibitors [MoA]; Cytochrome P450 2C9 Inducers [MoA]; Cytochrome P450 3A Inhibitors [MoA]; Cytomegalovirus DNA Terminase Complex Inhibitor [EPC]; DNA Terminase Complex Inhibitors [MoA]; Organic Anion Transporting Polypeptide 1B1 Inhibitors [MoA]; Organic Anion Transporting Polypeptide 1B3 Inhibitors [MoA]; Cytochrome P450 2C19 Inducers [MoA]

5.4 ATC Code

J05

J - Antiinfectives for systemic use

J05 - Antivirals for systemic use

J05A - Direct acting antivirals

J05AX - Other antivirals

J05AX18 - Letermovir

5.5 Absorption, Distribution and Excretion

Absorption

Letermovir has a bioavailability of 94% in healthy subjects when administered without cyclosporin, 35% in HSCT recipients when administered without cyclosporin, and 85% in HSCT recipients when administered with cyclosporin. Letermovir's Tmax is 45 min to 2.25 h. Time to steady state has been observed to be 9-10 days. Taking Letermovir with food increases Cmax by an average of 129.82% (range of 104.35%-161.50%). No significant effect on AUC has been observed .

Route of Elimination

Letemovir is taken up by the liver through OATP1B1/3 transporters. 93% is excreted in the feces with 70% as the parent drug. <2% is excreted in the urine.

Volume of Distribution

The mean steady state volume of distrubution is 45.5L

Clearance

The mean clearance is 11.25 L/h in healthy subjects

5.6 Metabolism/Metabolites

Letermovir undergoes a minor degree of metabolism through UGT1A1/1A3.

5.7 Biological Half-Life

The mean terminal half-life was observed to be 12 hours following administration of Letemovir 480 mg IV once daily.

5.8 Mechanism of Action

CMV relies on a DNA terminase complex consisting of multiple subunits (pUL51, pUL56, and pUL89) for processing of viral DNA. Viral DNA is produced in a single repeating strand which is then cut by the DNA terminase complex into individual viral genomes which can then be packaged into mature viral particles. Letemovir inhibits the activity of this complex to prevent production of mature viral genomes and the production of viable viral particles. The exact nature of Letemovir's binding to this complex is not currently known. Initially, the observation of resistance-causing mutations in pUL56 suggested this subunit was the location of Letemovir binding. However, resistance mutations have now been observed in pUL51, pUL56, and pUL89. It is possible that changes in amino acid sequence in one subunit could result in conformational changes to interacting subunits affecting Letemovir binding or that Letemovir interacts with multiple subunits of the complex but evidence towards either of these distinctions has not yet been seen. pUL89 is known to contain the endonuclease activity of the complex but because all members of the complex are necessary for targeting as well as protection from proteosomal degradation, it is difficult to discern if Letemovir inhibits pUL89's activity directly.

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