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Brincidofovir

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Synopsis

ACTIVE PHARMA INGREDIENTS

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Chemistry

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Also known as: 444805-28-1, Cmx001, Cmx 001, Hdp-cidofovir, Hexadecyloxypropyl-cidofovir, Hdp-cdv

Molecular Formula

C₂₇H₅₂N₃O₇P

Molecular Weight

561.7 g/mol

InChI Key

WXJFKKQWPMNTIM-VWLOTQADSA-N

FDA UNII

6794O900AX

Brincidofovir is an alkoxyalkyl ester prodrug containing the synthetic, acyclic nucleoside monophosphate analog cidofovir linked, through its phosphonate group, to a lipid, 3-hexadecyloxy-1-propanol, with antiviral activity against double-stranded DNA viruses. Upon oral administration, brincidofovir crosses the intestinal wall and penetrates target viral-infected cells before being cleaved to the free antiviral agent cidofovir. In turn, cidofovir is phosphorylated by pyruvate kinases to its active metabolite cidofovir diphosphate. Cidofovir diphosphate, bearing structural similarity to nucleotides, competes with deoxycytosine-5-triphosphate (dCTP) for viral DNA polymerase and gets incorporated into the growing viral DNA strands. As a result, it prevents further DNA polymerization and disrupts DNA replication of viruses. Compared to cidofovir, which is given intravenously, hexadecyloxypropyl-cidofovir shows better oral bioavailability, less toxicity and enhanced cellular penetration.

1 2D Structure

Brincidofovir

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

[(2S)-1-(4-amino-2-oxopyrimidin-1-yl)-3-hydroxypropan-2-yl]oxymethyl-(3-hexadecoxypropoxy)phosphinic acid

2.1.2 InChI

InChI=1S/C27H52N3O7P/c1-2-3-4-5-6-7-8-9-10-11-12-13-14-15-19-35-20-16-21-37-38(33,34)24-36-25(23-31)22-30-18-17-26(28)29-27(30)32/h17-18,25,31H,2-16,19-24H2,1H3,(H,33,34)(H2,28,29,32)/t25-/m0/s1

2.1.3 InChI Key

WXJFKKQWPMNTIM-VWLOTQADSA-N

2.1.4 Canonical SMILES

CCCCCCCCCCCCCCCCOCCCOP(=O)(COC(CN1C=CC(=NC1=O)N)CO)O

2.1.5 Isomeric SMILES

CCCCCCCCCCCCCCCCOCCCOP(=O)(CO[C@@H](CN1C=CC(=NC1=O)N)CO)O

2.2 Other Identifiers

2.2.1 UNII

6794O900AX

2.3 Synonyms

2.3.1 MeSH Synonyms

1. Cidofovir Hexadecyloxypropyl Ester

2. Cmx 001

3. Cmx-001

4. Cmx001

5. Hdp-cdv

6. Hexadecyloxypropyl Cidofovir

7. Tembexa

2.3.2 Depositor-Supplied Synonyms

1. 444805-28-1

2. Cmx001

3. Cmx 001

4. Hdp-cidofovir

5. Hexadecyloxypropyl-cidofovir

6. Hdp-cdv

7. Cmx-001

8. Hexadecyloxypropyl Cidofovir

9. Tembexa

10. Brincidofovir [usan]

11. [(2s)-1-(4-amino-2-oxopyrimidin-1-yl)-3-hydroxypropan-2-yl]oxymethyl-(3-hexadecoxypropoxy)phosphinic Acid

12. 6794o900ax

13. Brincidofovir (usan)

14. 3-(hexadecyloxy)propyl Hydrogen ((((s)-1-(4-amino-2-oxopyrimidin-1(2h)-yl)-3-hydroxypropan-2-yl)oxy)methyl)phosphonate

15. Phosphonic Acid, P-(((1s)-2-(4-amino-2-oxo-1(2h)-pyrimidinyl)-1-(hydroxymethyl)ethoxy)methyl)-, Mono(3-(hexadecyloxy)propyl) Ester

16. Cidofovir-hdp

17. Brincidofovir [usan:inn]

18. Hexadecyloxypropyl - Cidofovir

19. Cidofovir Prodrug

20. Unii-6794o900ax

21. Cidofovir Hexadecyloxypropyl Ester

22. Hdp-hpmpc

23. Brincidofovir; Cmx001

24. Hdp-cdvcmx001

25. Brincidofovir [inn]

26. Cmx001;hdp-cdv

27. Brincidofovir (cmx-001)

28. 1-o-hexadecylpropanediol-cdv

29. Schembl139922

30. Brincidofovir [who-dd]

31. Chembl203321

32. Gtpl11556

33. Dtxsid60196190

34. Brincidofovir [orange Book]

35. Bcp08580

36. Ex-a2366

37. Nsc783202

38. Zinc14141521

39. Db12151

40. Nsc-783202

41. Ncgc00686671-01

42. Ac-36043

43. A13326

44. D10547

45. Q15411004

46. C525733000

47. [(1s)-1-[(4-amino-2-oxo-pyrimidin-1-yl)methyl]-2-hydroxy-ethoxy]methyl-(3-hexadecoxypropoxy)phosphinic Acid

48. [[(s)-2-(4-amino-2-oxo-1,2-dihydropyrimidine-1-yl)-1-(hydroxymethyl)ethoxy]methyl]phosphonic Acid 3-(hexadecyloxy)propyl Ester

49. 3-((2s)-2-{[(3-hexadecyloxypropoxy)(hydroxyphosphoryl)]methoxy}-3-hydroxypropyl)-6-amino-3-hydropyrimidin-2-one

2.4 Create Date

2005-08-01

3 Chemical and Physical Properties

Molecular Formula	C₂₇H₅₂N₃O₇P
Molecular Weight	561.7 g/mol
XLogP3	4.9
Hydrogen Bond Donor Count	3
Hydrogen Bond Acceptor Count	7
Rotatable Bond Count	26
Exact Mass	561.35428800 g/mol
Monoisotopic Mass	561.35428800 g/mol
Topological Polar Surface Area	144 Å²
Heavy Atom Count	38
Formal Charge	0
Complexity	721
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

Brincidofovir is indicated for the treatment of human smallpox disease in adult and pediatric patients.

Treatment of adenovirus in immunocompromised patients

Treatment of smallpox

5 Pharmacology and Biochemistry

5.1 Pharmacology

The pharmacologically active agent resulting from brincidofovir metabolism, cidofovir diphosphate, has an exceedingly long duration of action that allows for it to be dosed once weekly. The entirety of a brincidofovir smallpox treatment consists of only two doses, on days 1 and 8, which seemingly reduces the risk of adverse reactions. Regimens involving a longer duration of administration (i.e. more than a single dose on days 1 and 8) have been shown to increase mortality compared to placebo and should therefore be avoided. Brincidofovir is considered a potential human carcinogen and has demonstrated the potential to cause infertility - as such, its use should be restricted to situations in which it is absolutely necessary.

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.)

5.3 ATC Code

J - Antiinfectives for systemic use

J05 - Antivirals for systemic use

J05A - Direct acting antivirals

J05AB - Nucleosides and nucleotides excl. reverse transcriptase inhibitors

J05AB17 - Brincidofovir

5.4 Absorption, Distribution and Excretion

Absorption

The oral bioavailability of brincidofovir is 13.4% in its tablet formulation and 16.8% in its suspension formulation. Following oral administration, the C_max and AUC_tau of brincidofovir were 480 ng/mL and 3400 nghr/mL, respectively. The C_max and AUC_tau of the active metabolite, cidofovir diphosphate, were 9.7 pg/10⁶ cells and 1200 pghr/10⁶ cells, respectively. Maximum plasma concentrations (T_max) of brincidofovir are reached at approximately 3 hours post-administration, while maximal plasma concentrations for cidofovir diphosphate are reached at approximately 47 hours post-administration.

Route of Elimination

Brincidofovir is eliminated as metabolites in both the urine (~51%) and feces (~40%).

Volume of Distribution

The apparent volume of distribution of brincidofovir is 1230 L.

Clearance

The apparent clearance of brincidofovir in healthy adult patients is 44.1 L/h.

5.5 Metabolism/Metabolites

Brincidofovir is a pro-drug of [cidofovir] and as such must undergo some basic metabolic reactions to become pharmacologically active. Upon entering the target cell, the phosphodiester bond of brincidofovir is hydrolyzed to generate cidofovir, which is then phosphorylated to generate the active agent: cidofovir diphosphate. The specific enzyme(s) responsible for this reaction have not been elucidated, but _in vitro_ findings suggest sphingomyelin phosphodiesterase plays a major role in the initial hydrolysis of brincidofovir. There are two major inactive metabolites of brincidofovir, CMX103 and CMX064, which are generated via carboxylation of the terminal carbon followed by several cycles of CYP-mediated oxidative reactions and fatty acid oxidation. These reactions are mediated, at least in part, by CYP4F2.

5.6 Biological Half-Life

The mean terminal half-lives of brincidofovir and its pharmacologically active metabolite, cidofovir diphosphate, are 19.3 hours and 113 hours, respectively.

5.7 Mechanism of Action

Brincidofovir is a pro-drug comprising [cidofovir] conjugated to a lipid molecule - the lipid component mimics an endogenous lipid, lysophosphatidylcholine, which allows the molecule to hijack endogenous lipid uptake pathways to enter infected cells. Following uptake, the lipid molecule is cleaved to generate cidofovir, which is then phosphorylated to generate the active antiviral compound, cidofovir disphosphate. The antiviral effects of cidofovir diphosphate appear to be the result of two distinct mechanisms. Mechanistic studies using recombinant vaccinia DNA polymerase suggest that it inhibits orthopoxvirus DNA polymerase-mediated DNA synthesis. In addition, cidofovir is an acyclic nucleotide analogue of deoxycytidine monophosphate - cidofovir diphosphate can therefore be incorporated into the growing viral DNA chain and consequently slow the rate of viral DNA synthesis.

Drugs in Development