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Belzutifan

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Chemistry

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Also known as: Pt2977, 1672668-24-4, Mk-6482, Welireg, Mk6482, Belzutifan [inn]

Molecular Formula

C₁₇H₁₂F₃NO₄S

Molecular Weight

383.3 g/mol

InChI Key

LOMMPXLFBTZENJ-ZACQAIPSSA-N

FDA UNII

7K28NB895L

Belzutifan is an orally active, small molecule inhibitor of hypoxia inducible factor (HIF)-2alpha (HIF-2a), with potential antineoplastic activity. Upon oral administration, belzutifan binds to and blocks the function of HIF-2alpha, thereby preventing HIF-2alpha heterodimerization and its subsequent binding to DNA. This results in decreased transcription and expression of HIF-2alpha downstream target genes, many of which regulate hypoxic signaling. This inhibits cell growth and survival of HIF-2alpha-expressing tumor cells. HIF-2alpha, the alpha subunit for the heterodimeric transcription factor HIF-2, is overexpressed in many cancers and promotes tumorigenesis.

1 2D Structure

Belzutifan

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

3-[[(1S,2S,3R)-2,3-difluoro-1-hydroxy-7-methylsulfonyl-2,3-dihydro-1H-inden-4-yl]oxy]-5-fluorobenzonitrile

2.1.2 InChI

InChI=1S/C17H12F3NO4S/c1-26(23,24)12-3-2-11(13-14(12)17(22)16(20)15(13)19)25-10-5-8(7-21)4-9(18)6-10/h2-6,15-17,22H,1H3/t15-,16-,17+/m1/s1

2.1.3 InChI Key

LOMMPXLFBTZENJ-ZACQAIPSSA-N

2.1.4 Canonical SMILES

CS(=O)(=O)C1=C2C(C(C(C2=C(C=C1)OC3=CC(=CC(=C3)C#N)F)F)F)O

2.1.5 Isomeric SMILES

CS(=O)(=O)C1=C2[C@@H]([C@@H]([C@@H](C2=C(C=C1)OC3=CC(=CC(=C3)C#N)F)F)F)O

2.2 Other Identifiers

2.2.1 UNII

7K28NB895L

2.3 Synonyms

2.3.1 MeSH Synonyms

1. 3-(((1s,2s,3r)-2,3-difluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1h-inden-4-yl)oxy)-5-fluorobenzonitrile

2. Mk-6482

3. Mk6482

4. Pt-2977

5. Pt2977

6. Welireg

2.3.2 Depositor-Supplied Synonyms

1. Pt2977

2. 1672668-24-4

3. Mk-6482

4. Welireg

5. Mk6482

6. Belzutifan [inn]

7. Belzutifan [usan]

8. Pt-2977

9. 3-(((1s,2s,3r)-2,3-difluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1h-inden-4-yl)oxy)-5-fluorobenzonitrile

10. 7k28nb895l

11. 3-[[(1s,2s,3r)-2,3-difluoro-1-hydroxy-7-methylsulfonyl-2,3-dihydro-1h-inden-4-yl]oxy]-5-fluorobenzonitrile

12. 3-{[(1s,2s,3r)-2,3-difluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1h-inden-4-yl]oxy}-5-fluorobenzonitrile

13. 3-((1s,2s,3r)-2,3-difluoro-1-hydroxy-7-methylsulfonylindan-4-yl)oxy-5-fluoro-benzonitrile

14. Benzonitrile, 3-(((1s,2s,3r)-2,3-difluoro-2,3-dihydro-1-hydroxy-7-(methylsulfonyl)-1h-inden-4-yl)oxy)-5-fluoro-

15. Belzutifan [who-dd]

16. Unii-7k28nb895l

17. Belzutifan [orange Book]

18. Chembl4585668

19. Schembl16560918

20. Gtpl11251

21. Pt 2977 [who-dd]

22. Bdbm373040

23. Dtxsid201334517

24. Pt 2977

25. Ex-a4441

26. Us9896418, Compound 289

27. Xrc66824

28. Nsc825217

29. Who 11196

30. At14994

31. Belzutifan (pt2977, Mk-6482)

32. Compound 2 [pmid: 31282155]

33. Nsc-825217

34. Mk-6482; Pt2977

35. Ac-35183

36. Hy-125840

37. Cs-0101119

38. A935088

39. Q27456641

40. 3-(((1s,2s,3r)-2,3-difluoro-1-hydroxy-7-(methanesulfonyl)-2,3-dihydro-1h-inden-4-yl)oxy)-5-fluorobenzonitrile

41. 3-((1s,2s,3r)-2,3-difluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1h-inden-4-yloxy)-5-fluorobenzonitrile

42. 72q

2.4 Create Date

2016-02-23

3 Chemical and Physical Properties

Molecular Formula	C₁₇H₁₂F₃NO₄S
Molecular Weight	383.3 g/mol
XLogP3	2
Hydrogen Bond Donor Count	1
Hydrogen Bond Acceptor Count	8
Rotatable Bond Count	3
Exact Mass	383.04391352 g/mol
Monoisotopic Mass	383.04391352 g/mol
Topological Polar Surface Area	95.8 Å²
Heavy Atom Count	26
Formal Charge	0
Complexity	675
Isotope Atom Count	0
Defined Atom Stereocenter Count	3
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

Belzutifan is indicated for the treatment of adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET), who do not require immediate surgery.

5 Pharmacology and Biochemistry

5.1 Pharmacology

Belzutifan exerts its therapeutic effects by inhibiting a transcription factor necessary for the growth of solid tumors associated with VHL disease. It is taken once daily at approximately the same time each day, with or without food. Both severe anemia and hypoxia have been observed following therapy with belzutifan, and patients should be monitored closely before and during therapy to ensure patients can be managed as clinically indicated. There are no data regarding the use of erythropoiesis-stimulating agents for the treatment of belzutifan-induced anemia, and as such these therapies should be avoided. Belzutifan may cause embryo-fetal toxicity when administered to pregnant women. Female patients and male patients with female partners of reproductive potential should ensure that an effective form of contraception is used throughout therapy and for one week after the last dose - as belzutifan appears to decrease the efficacy of systemic hormonal contraceptives, patients should be advised to use an additional method of contraception (e.g. condoms) to eliminate the possibility of pregnancy during therapy.

5.2 MeSH Pharmacological Classification

Antineoplastic Agents

Substances that inhibit or prevent the proliferation of NEOPLASMS. (See all compounds classified as Antineoplastic Agents.)

5.3 ATC Code

L - Antineoplastic and immunomodulating agents

L01 - Antineoplastic agents

L01X - Other antineoplastic agents

L01XX - Other antineoplastic agents

L01XX74 - Belzutifan

5.4 Absorption, Distribution and Excretion

Absorption

In patients with VHL disease-associated renal cell carcinoma, the mean C_max and AUC_0-24h at steady-state - which was achieved after approximately three days of therapy - were 1.3 g/mL and 16.7 ghr/mL, respectively. The median T_max is one to two hours following oral administration. The administration of belzutifan with food has a negligible effect on drug disposition - when given alongside a high-calorie, high-fat meal, the T_max was delayed by approximately 2 hours with no other clinically meaningful effects observed.

Volume of Distribution

The steady-state volume of distribution of belzutifan following oral administration is approximately 130 L.

Clearance

The mean clearance of belzutifan following oral administration is 7.3 L/h.

5.5 Metabolism/Metabolites

Belzutifan is primarily metabolized by UGT2B17 and CYP2C19, and to a lesser extent by CYP3A4.

5.6 Biological Half-Life

The mean elimination half-life of belzutifan is 14 hours.

5.7 Mechanism of Action

Hypoxia-inducible factor 2 (HIF-2) is a transcription factor which aids in oxygen sensing by regulating genes that promote adaptation to hypoxia. In healthy patients, when oxygen levels are normal, HIF-2 is broken down via ubiquitin-proteasomal degradation by von-Hippel Lindau (VHL) proteins. In the presence of hypoxia, HIF-2 translocates into cell nuclei and forms a transcriptional complex with hypoxia-inducible factor 1 (HIF-1) - this complex then induces the expression of downstream genes associated with cellular proliferation and angiogenesis. Patients with von-Hippel Lindau (VHL) disease lack functional VHL proteins, leading to an accumulation of HIF-2, and this accumulation is what drives the growth of VHL-associated tumors. Belzutifan is an inhibitor of HIF-2 that prevents its complexation with HIF-1 in conditions of hypoxia or impaired VHL protein function, thereby reducing the expression of HIF-2 target genes and slowing/stopping the growth of VHL-associated tumors.

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