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Fostemsavir

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Chemistry

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Also known as: 864953-29-7, Bms-663068, Bms-663068 free acid, Bms 663068, Fostemsavir [usan], Rukobia

Molecular Formula

C₂₅H₂₆N₇O₈P

Molecular Weight

583.5 g/mol

InChI Key

SWMDAPWAQQTBOG-UHFFFAOYSA-N

FDA UNII

97IQ273H4L

Fostemsavir is the phosphonooxymethyl prodrug of temsavir, a novel HIV-1 attachment inhibitor. It binds to and inhibits the activity of gp120, a subunit within the HIV-1 gp160 envelope glycoprotein that facilitates the attachment of HIV-1 to host cell CD4 receptors - in doing so, temsavir prevents the first step in the HIV-1 viral lifecycle. The discovery of gp120 as a potential target of interest in the treatment of HIV-1 infection is relatively recent, and was born out of a desire to find alternative target proteins (i.e. mechanistically orthogonal therapies) for the treatment of HIV-1 patients with resistant infections. Fostemavir is the first attachment inhibitor to receive FDA approval, granted in July 2020 for use in combination with other antiretrovirals in highly treatment-experienced patients with multidrug-resistant HIV-1 infection whom are failing their current therapy. Targeting gp120 subunits is a new and novel therapeutic approach to HIV-1 infection, and the addition of attachment inhibitors, like temsavir, to the armament of therapies targeted against HIV-1 fills a necessary niche for therapeutic options in patients left with few, if any, viable treatments.

1 2D Structure

Fostemsavir

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

[3-[2-(4-benzoylpiperazin-1-yl)-2-oxoacetyl]-4-methoxy-7-(3-methyl-1,2,4-triazol-1-yl)pyrrolo[2,3-c]pyridin-1-yl]methyl dihydrogen phosphate

2.1.2 InChI

InChI=1S/C25H26N7O8P/c1-16-27-14-32(28-16)23-21-20(19(39-2)12-26-23)18(13-31(21)15-40-41(36,37)38)22(33)25(35)30-10-8-29(9-11-30)24(34)17-6-4-3-5-7-17/h3-7,12-14H,8-11,15H2,1-2H3,(H2,36,37,38)

2.1.3 InChI Key

SWMDAPWAQQTBOG-UHFFFAOYSA-N

2.1.4 Canonical SMILES

CC1=NN(C=N1)C2=NC=C(C3=C2N(C=C3C(=O)C(=O)N4CCN(CC4)C(=O)C5=CC=CC=C5)COP(=O)(O)O)OC

2.2 Other Identifiers

2.2.1 UNII

97IQ273H4L

2.3 Synonyms

2.3.1 MeSH Synonyms

1. (3-((4-benzoyl-1-piperazinyl)(oxo)acetyl)-4-methoxy-7-(3-methyl-1h-1,2,4-triazol-1-yl)-1h-pyrrolo(2,3-c)pyridin-1-yl)methyl Dihydrogen Phosphate

2. 1,2-ethanedione, 1-(4-benzoyl-1-piperazinyl)-2-(4-methoxy-7-(3-methyl-1h-1,2,4-triazol-1-yl)-1-((phosphonooxy)methyl)-1h-pyrrolo(2,3-c)pyridin-3-yl)-

3. Bms-663068

2.3.2 Depositor-Supplied Synonyms

1. 864953-29-7

2. Bms-663068

3. Bms-663068 Free Acid

4. Bms 663068

5. Fostemsavir [usan]

6. Rukobia

7. Fostemsavir(bms-663068)

8. 97iq273h4l

9. 864953-29-7(free Base)

10. Fostemsavir (usan)

11. [3-[2-(4-benzoylpiperazin-1-yl)-2-oxoacetyl]-4-methoxy-7-(3-methyl-1,2,4-triazol-1-yl)pyrrolo[2,3-c]pyridin-1-yl]methyl Dihydrogen Phosphate

12. Bms663068

13. Piperazine, 1-benzoyl-4-((4-methoxy-7-(3-methyl-1h-1,2,4-triazol-1-yl)-1-((phosphonooxy)methyl)-1h-pyrrolo(2,3-c)pyridin-3-yl)oxoacetyl)-

14. (3-(2-(4-benzoylpiperazin-1-yl)-2-oxoacetyl)-4-methoxy-7-(3-methyl-1h-1,2,4-triazol-1-yl)-1h-pyrrolo[2,3-c]pyridin-1-yl)methyl Dihydrogen Phosphate

15. Unii-97iq273h4l

16. Fostemsavir & N6

17. [3-[2-(4-benzoylpiperazin-1-yl)-2-oxo-acetyl]-4-methoxy-7-(3-methyl-1,2,4-triazol-1-yl)pyrrolo[2,3-c]pyridin-1-yl]methyl Dihydrogen Phosphate

18. 1,2-ethanedione, 1-(4-benzoyl-1-piperazinyl)-2-(4-methoxy-7-(3-methyl-1h-1,2,4-triazol-1-yl)-1-((phosphonooxy)methyl)-1h-pyrrolo(2,3-c)pyridin-3-yl)-

19. 1,2-ethanedione, 1-(4-benzoyl-1-piperazinyl)-2-[4-methoxy-7-(3-methyl-1h-1,2,4-triazol-1-yl)-1-[(phosphonooxy)methyl]-1h-pyrrolo[2,3-c]pyridin-3-yl]-

20. Gsk3684934

21. Fostemsavir & Pg16

22. Fostemsavir & 4dm2m

23. Fostemsavir & Vrc03

24. Fostemsavir & Ch106

25. Fostemsavir & 35o22

26. Fostemsavir & Pgt128

27. Fostemsavir [mi]

28. Fostemsavir [inn]

29. Fostemsavir & 3bnc117

30. Fostemsavir & Pg16-imab

31. Fostemsavir [who-dd]

32. Fostemsavir & Pgt128-imab

33. Fostemsavir & Vrc07-523

34. Schembl754395

35. Fostemsavir; Bms-663068

36. Chembl3301594

37. Gtpl11100

38. Dtxsid40235596

39. Fostemsavir & Nih45-46g54w

40. Bcp13226

41. Ex-a1973

42. Bms-626529 & 4dm2m

43. Hy-15440a

44. S7220

45. Zinc14210883

46. Bms-626529 & Pg16-imab

47. Bms-663038

48. Cs-1059

49. Db11796

50. Sb11250

51. Bms-626529 & Pgt128-imab

52. Bms626-529 & Vrc03

53. Gsk-3684934

54. Bms-626529 & N6

55. Bms-626529 & Pg16

56. Compound 35 [pmid: 29271653]

57. Ncgc00510187-01

58. Ac-30663

59. Bms-626529 & Pgt128

60. Bms-626529 & Ch106

61. Bms-626529 & 3bnc117

62. Bms-626529 & 35o22

63. Bms-626529 & Vrc07-523

64. Bms626-529 & Nih45-46g54w

65. D10707

66. A863152

67. Q17001240

68. ({3-[2-(4-benzoylpiperazin-1-yl)-2-oxoacetyl]-4-methoxy-7-(3-methyl-1h-1,2,4-triazol-1-yl)-1h-pyrrolo[2,3-c]pyridin-1-yl}methoxy)phosphonic Acid

69. (3-((4-benzoyl-1-piperazinyl)(oxo)acetyl)-4-methoxy-7-(3-methyl-1h-1,2,4-triazol-1-yl)-1h-pyrrolo(2,3-c)pyridin-1-yl)methyl Dihydrogen Phosphate

70. (3-((4-benzoylpiperazin-1-yl)-oxoacetyl)-4-methoxy- 7-(3-methyl-1h-1,2,4-triazol-1-yl)-1h-pyrrolo(2,3-c)pyridin- 1-yl)methyl Dihydrogen Phosphate

71. 1-(4-benzoyl-1-piperazinyl)-2-[4-methoxy-7-(3-methyl-1h-1,2,4-triazol-1-yl)-1-[(phosphonooxy)methyl]-1h-pyrrolo[2,3-c]pyridin-3-yl]-1,2-ethanedione

2.4 Create Date

2006-10-26

3 Chemical and Physical Properties

Molecular Formula	C₂₅H₂₆N₇O₈P
Molecular Weight	583.5 g/mol
XLogP3	-0.1
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	11
Rotatable Bond Count	8
Exact Mass	583.15804781 g/mol
Monoisotopic Mass	583.15804781 g/mol
Topological Polar Surface Area	182 Å²
Heavy Atom Count	41
Formal Charge	0
Complexity	1020
Isotope Atom Count	0
Defined Atom Stereocenter Count	0
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

Fostemsavir is indicated, in combination with other antiretrovirals, for the treatment of multidrug-resistant HIV-1 infection in heavily treatment-experienced adults failing their current antiretroviral therapy due to resistance, intolerance, or safety concerns.

Rukobia, in combination with other antiretrovirals, is indicated for the treatment of adults with multidrug resistant HIV-1 infection for whom it is otherwise not possible to construct a suppressive anti-viral regimen.

5 Pharmacology and Biochemistry

5.1 Pharmacology

Temsavir inhibits the first stage in the HIV-1 viral lifecycle: attachment. It has a moderate duration of action necessitating twice-daily dosing. Fostemsavir, administered at roughly 4x the recommended human dose, has been observed to significantly prolong the QTc-interval. Patients with a history of QTc-prolongation, those receiving other QTc-prolonging medications, and/or those with pre-existing cardiac disease should use fostemsavir with caution, and should be monitored at baseline and throughout therapy for signs or symptoms suggestive of QTc-prolongation. Fostemsavir should also be used with caution in patients with hepatitis B or C co-infection as elevations in hepatic transaminases were observed in greater proportions in these populations in clinical trials.

5.2 MeSH Pharmacological Classification

Anti-HIV Agents

Agents used to treat AIDS and/or stop the spread of the HIV infection. These do not include drugs used to treat symptoms or opportunistic infections associated with AIDS. (See all compounds classified as Anti-HIV Agents.)

HIV Fusion Inhibitors

Inhibitors of the fusion of HIV to host cells, preventing viral entry. This includes compounds that block attachment of HIV ENVELOPE PROTEIN GP120 to CD4 RECEPTORS. (See all compounds classified as HIV Fusion Inhibitors.)

5.3 ATC Code

J05AX

J - Antiinfectives for systemic use

J05 - Antivirals for systemic use

J05A - Direct acting antivirals

J05AX - Other antivirals

J05AX29 - Fostemsavir

5.4 Absorption, Distribution and Excretion

Absorption

The absorption of temsavir is significantly limited by suboptimal dissolution and solubility following oral administration. Fostemsavir, a phosphonooxymethyl prodrug of temsavir, has improved aqueous solubility and stability under acidic conditions as compared to its parent drug - following oral administration of fostemsavir, the absolute bioavailability is approximately 26.9%. The C_max and AUC_tau following oral administration of fostemsavir 600mg twice daily was 1770 ng/mL and 12,900 ng.h/L, respectively, with a T_max of approximately 2 hours. Co-administration of fostemsavir with a standard meal increases its AUC by approximately 10%, while co-administration with a high-fat meal increases its AUC by approximately 81%.

Route of Elimination

Temsavir is highly metabolized, after which it is excreted in the urine and feces as inactive metabolites. Approximately 51% of a given dose is excreted in the urine, with <2% comprising unchanged parent drug, and 33% is excreted in the feces, of which 1.1% is unchanged parent drug.

Volume of Distribution

The steady-state volume of distribution of temsavir following intravenous administration is approximately 29.5 L.

Clearance

The mean clearance and apparent clearance of temsavir, the active metabolite of fostemsavir, are 17.9 L/h and 66.4 L/h, respectively.

5.5 Metabolism/Metabolites

Fostemsavir is rapidly hydrolyzed to temsavir, its active metabolite, by alkaline phosphatase(s) present at the brush border membrane of the intestinal lumen. Temsavir undergoes further biotransformation to two predominant inactive metabolites: BMS-646915, a product of hydrolysis by esterases, and BMS-930644, an N-dealkylated metabolite generated via oxidation by CYP3A4. Approximately 36.1% of an administered oral dose is metabolized by esterases, 21.2% is metabolized by CYP3A4, and <1% is conjugated by UDP-glucuronosyltransferases (UGT) prior to elimination. Both temsavir and its two predominant metabolites are known to inhibit BCRP.

5.6 Biological Half-Life

The half-life of temsavir is approximately 11 hours. Fostemsavir is generally undetectable in plasma following oral administration.

5.7 Mechanism of Action

The gp120 subunit within the gp160 envelope glycoprotein of HIV-1 is a new and novel target in the treatment of HIV-1 infection. These subunits are responsible for facilitating the first step in the viral life cycle, attachment, by mediating the interaction between the virus and host cell CD4 receptors. Following attachment, HIV-1 undergoes assembly, budding, and maturation within the host cell, after which mature viral particles are released to continue the viral life cycle. Fostemsavir's active metabolite, temsavir, is an HIV-1 attachment inhibitor. It binds directly to the gp120 subunit to inhibit viral interaction with host CD4 receptors, thereby preventing the initial attachment required for viral replication. It has also been shown to inhibit other gp120-dependent post-attachment steps required for viral entry.

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