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Voclosporin

Voclosporin

Synopsis, Chemistry

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Also known as: 515814-01-4, Lupkynis, Luveniq, Isatx-247, Voclosporin [usan], Isatx247

Molecular Formula

C₆₃H₁₁₁N₁₁O₁₂

Molecular Weight

1214.6 g/mol

InChI Key

BICRTLVBTLFLRD-PTWUADNWSA-N

FDA UNII

2PN063X6B1

Lupus nephritis (LN) is a type of glomerulonephritis occurring in patients with systemic lupus erythematosus (SLE). LN is a significant cause of renal failure, morbidity, and death in patients with SLE. Within 10 years of being diagnosed with SLE, 5-20% of those suffering from LN develop end-stage kidney disease, a fatal condition. Early and accurate intervention for LN is important in improving clinical outcomes. Voclosporin, marketed as Lupkynis, is a calcineurin-inhibitor immunosuppressant for the treatment of LN. This [cyclosporine] A analog was approved by the FDA on January 22, 2021 following promising results in clinical trials. Early intervention with voclosporin coupled with a kidney response is believed to prevent irreversible damage to the kidney and lead to better long-term clinical outcomes for patients with LN. Voclosporin has demonstrated a more stable pharmacokinetic and pharmacodynamic relationship than cyclosporine, a higher potency than cyclosporine, and an improved metabolic profile when compared to older calcineurin inhibitors.

Voclosporin is a Calcineurin Inhibitor Immunosuppressant. The mechanism of action of voclosporin is as a Calcineurin Inhibitor, and P-Glycoprotein Inhibitor, and Organic Anion Transporting Polypeptide 1B1 Inhibitor, and Organic Anion Transporting Polypeptide 1B3 Inhibitor.

1 2D Structure

Voclosporin

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

(3S,6S,9S,12R,15S,18S,21S,24S,30S,33S)-30-ethyl-33-[(1R,2R,4E)-1-hydroxy-2-methylhepta-4,6-dienyl]-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone

2.1.2 InChI

InChI=1S/C63H111N11O12/c1-25-27-28-29-41(15)53(76)52-57(80)66-44(26-2)59(82)68(18)34-49(75)69(19)45(30-35(3)4)56(79)67-50(39(11)12)62(85)70(20)46(31-36(5)6)55(78)64-42(16)54(77)65-43(17)58(81)71(21)47(32-37(7)8)60(83)72(22)48(33-38(9)10)61(84)73(23)51(40(13)14)63(86)74(52)24/h25,27-28,35-48,50-53,76H,1,26,29-34H2,2-24H3,(H,64,78)(H,65,77)(H,66,80)(H,67,79)/b28-27+/t41-,42+,43-,44+,45+,46+,47+,48+,50+,51+,52+,53-/m1/s1

2.1.3 InChI Key

BICRTLVBTLFLRD-PTWUADNWSA-N

2.1.4 Canonical SMILES

CCC1C(=O)N(CC(=O)N(C(C(=O)NC(C(=O)N(C(C(=O)NC(C(=O)NC(C(=O)N(C(C(=O)N(C(C(=O)N(C(C(=O)N(C(C(=O)N1)C(C(C)CC=CC=C)O)C)C(C)C)C)CC(C)C)C)CC(C)C)C)C)C)CC(C)C)C)C(C)C)CC(C)C)C)C

2.1.5 Isomeric SMILES

CC[C@H]1C(=O)N(CC(=O)N([C@H](C(=O)N[C@H](C(=O)N([C@H](C(=O)N[C@H](C(=O)N[C@@H](C(=O)N([C@H](C(=O)N([C@H](C(=O)N([C@H](C(=O)N([C@H](C(=O)N1)[C@@H]([C@H](C)C/C=C/C=C)O)C)C(C)C)C)CC(C)C)C)CC(C)C)C)C)C)CC(C)C)C)C(C)C)CC(C)C)C)C

2.2 Other Identifiers

2.2.1 UNII

2PN063X6B1

2.3 Synonyms

2.3.1 MeSH Synonyms

1. Isa 247

2. Isa(tx)247

3. Isa-247

4. Isatx247

5. Lupkynis

2.3.2 Depositor-Supplied Synonyms

1. 515814-01-4

2. Lupkynis

3. Luveniq

4. Isatx-247

5. Voclosporin [usan]

6. Isatx247

7. Isa-247

8. Isa247

9. Lx211

10. Lx-211

11. R 1524

12. R-1524

13. Isa(tx)247

14. (3s,6s,9s,12r,15s,18s,21s,24s,30s,33s)-30-ethyl-33-[(1r,2r,4e)-1-hydroxy-2-methylhepta-4,6-dienyl]-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone

15. 515814-00-3

16. 2pn063x6b1

17. Trans-isa 247

18. Voclera

19. Isa 247

20. (3s,6s,9s,12r,15s,18s,21s,24s,30s,33s)-30-ethyl-33-((1r,2r,e)-1-hydroxy-2-methylhepta-4,6-dien-1-yl)-6,9,18,24-tetraisobutyl-3,21-diisopropyl-1,4,7,10,12,15,19,25,28-nonamethyl-1,4,7,10,13,16,19,22,25,28,31-undecaazacyclotritriacontan-2,5,8,11,14,17,20,23,26,29,32-undecaone

21. Trans-isa-247

22. Voclosporin (usan/inn)

23. Voclosporin [usan:inn]

24. Isatx 247

25. Unii-2pn063x6b1

26. 3odi

27. Lx-214

28. Isatx-247; Luveniq

29. Voclosporin [mi]

30. Voclosporin [inn]

31. Voclosporin [mart.]

32. Voclosporin [who-dd]

33. E-isa247

34. Schembl12632344

35. Gtpl11388

36. Voclosporin [orange Book]

37. Chebi:135957

38. Dtxsid401030488

39. (e)-isa-247

40. Ex-a5922

41. At27977

42. Db11693

43. Hy-106638

44. Cs-0026210

45. R1524

46. D09033

47. Q7939256

48. Cyclosporin A, 6-((2s,3r,4r)-3-hydroxy-4-methyl-2-(methylamino)-6,8-nonadienoic Acid)-

49. (3s,6s,9s,12r,15s,18s,21s,24s,30s,33s)-30-ethyl-33-[(1r,2r,4e)-1-hydroxy-2-methylhepta-4,6-dien-1-yl]-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21-bis(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecaazacyclotritriacontan-2,5,8,11,14,17,20,23,26,29,32-undecone

50. 1,11-anhydro[l-alanyl-d-alanyl-n-methyl-l-leucyl-n-methyl-l-leucyl- N-methyl-l-valyl-[(2s,3r,4r,6e)-3-hydroxy-4-methyl- 2-(methylamino)nona-6,8-dienoyl][(2s)-2-aminobutanoyl]- N-methylglycyl-n-methyl-l-leucyl-l-valyl-n-methyl-l-leucine]

51. Cyclo (((e,z)-(2s,3r,4r)-3-hydroxy-4-methyl-2-(methylamino)nona-6,8-dienoyl)-l-2-aminobytyrl-n-methyl-glycyl-n-methyl-l-leucyl-l-valyl-n-methyl-l-leucyl-l-alanyl-d-alanyl-n-methyl-l-leucyl-n-methyl-l-leucyl-n-methyl-l-valyl)

52. Cyclo(l-alanyl-d-alanyl-n-methyl-l-leucyl-n-methyl-l-leucyl-n-methyl-l-valyl- ((2s,3r,4r,6e)-3-hydroxy-4-methyl-2-(methylamino)nona-6,8-dienoyl)-(2s)-2- Aminobutanoyl-n-methylglycyl-n-methyl-l-leucyl-l-valyl-n-methyl-l-leucyl)

53. Cyclosporin A, 6-((2s,3r,4r,6e)-3-hydroxy-4-methyl-2-(methylamino)-6,8- Nonadienoic Acid)-

2.4 Create Date

2006-07-28

3 Chemical and Physical Properties

Molecular Formula	C₆₃H₁₁₁N₁₁O₁₂
Molecular Weight	1214.6 g/mol
XLogP3	7.9
Hydrogen Bond Donor Count	5
Hydrogen Bond Acceptor Count	12
Rotatable Bond Count	16
Exact Mass	1213.84136802 g/mol
Monoisotopic Mass	1213.84136802 g/mol
Topological Polar Surface Area	279 Å²
Heavy Atom Count	86
Formal Charge	0
Complexity	2380
Isotope Atom Count	0
Defined Atom Stereocenter Count	12
Undefined Atom Stereocenter Count	0
Defined Bond Stereocenter Count	1
Undefined Bond Stereocenter Count	0
Covalently Bonded Unit Count	1

4 Drug and Medication Information

4.1 Drug Indication

Voclosporin is used in combination with a background immunosuppressive regimen for the treatment of lupus nephritis. Safety has not been established in combination with cyclophosphamide.

Treatment of Systemic Lupus Erythematosus (SLE)

Treatment of non-infectious uveitis

Lupkynis is indicated in combination with mycophenolate mofetil for the treatment of adult patients with active class III, IV or V (including mixed class III/V and IV/V) lupus nephritis (LN).

5 Pharmacology and Biochemistry

5.1 Pharmacology

Voclosporin inhibits calcineurin, leading to the inhibition of T cell activation by blocking the transcription of early inflammatory cytokines. This reduces inflammation in the kidney, treating lupus nephritis and preventing permanent renal damage.

5.2 FDA Pharmacological Classification

5.2.1 Active Moiety

VOCLOSPORIN

5.2.2 FDA UNII

2PN063X6B1

5.2.3 Pharmacological Classes

Calcineurin Inhibitors [MoA]; Organic Anion Transporting Polypeptide 1B1 Inhibitors [MoA]; Organic Anion Transporting Polypeptide 1B3 Inhibitors [MoA]; P-Glycoprotein Inhibitors [MoA]; Calcineurin Inhibitor Immunosuppressant [EPC]

5.3 ATC Code

L04AD03

L - Antineoplastic and immunomodulating agents

L04 - Immunosuppressants

L04A - Immunosuppressants

L04AD - Calcineurin inhibitors

L04AD03 - Voclosporin

5.4 Absorption, Distribution and Excretion

Absorption

When administered on an empty stomach, the median Tmax of voclosporin is 1.5 hours, but can range from 1-4 hours. The AUC is estimated at 7693.6 ng/mL*h and the Cmax is estimated at 955.5 ng/mL.

Route of Elimination

Voclosporin is eliminated in the urine and feces, with about 88% detected in the feces and about 2% detected in the urine.

Volume of Distribution

The apparent volume of distribution of voclosporin is 2,154 L. Voclosporin distributes extensively into red blood cells; distribution between whole blood and plasma is dependent on concentration and temperature.

Clearance

The mean apparent steady-state clearance of voclosporin is 63.6 L/h. Hepatic and renal impairment significantly reduce the clearance of voclosporin.

5.5 Metabolism/Metabolites

Voclosporin is mainly metabolized by the CYP3A4 hepatic cytochrome enzyme. Pharmacologic activity is mainly attributed to the parent molecule. A major metabolite has been detected in human whole blood, representing 16.7% of total exposure; this metabolite is about 8-fold less potent than the parent drug, voclosporin.

5.6 Biological Half-Life

The average terminal half-life of voclosporin is about 30 hours (24.9 to 36.5 hours).

5.7 Mechanism of Action

Through the inhibition of calcineurin, voclosporin blocks IL-2 expression and T-cell mediated immune responses, stabilizing podocytes in the kidneys. Voclospoprin is a cyclosporine A analog. It is structurally similar to cyclosporine A (CsA) with the exception of an amino acid modification in one region. This modification changes the binding of voclosporin to calcineurin. Cyclosporine inhibitors reversibly inhibit T-lymphocytes. They also inhibit lymphokine production and release. Cyclosporine A exerts its inhibitory effects on T-lymphocytes by binding to cyclophilin. A cyclophilin-cyclosporine complex is formed, leading to the inhibition of calcium- and calmodulin-dependent serine-threonine phosphatase activity of calcineurin. Along with calcineurin inhibition, the inhibition of many transcription factors necessary for the induction of various cytokine genes such as IL-2, IFN-, IL-4 and GM-CSF occurs. This, in turn, reduces inflammation, treating renal glomerulonephritis associated with systemic lupus erythematosus.