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Difelikefalin

Difelikefalin

Synopsis, Chemistry

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Also known as: 1024828-77-0, Cr845, Difelikefalin [inn], Mr13a9, Cr-845, Korsuva

Molecular Formula

C₃₆H₅₃N₇O₆

Molecular Weight

679.8 g/mol

InChI Key

FWMNVWWHGCHHJJ-SKKKGAJSSA-N

FDA UNII

NA1U919MRO

Difelikefalin (CR845) is an agonist of kappa opioid receptors (KORs) useful in the treatment of pruritus secondary to chronic kidney disease. KORs were first associated with itching in 1984. Further investigations revealed that dynorphins, endogenous agonists of KORs, work to inhibit the itching sensation at the spinal cord level, and scratching could be elicited in mouse models with the administration of KOR antagonists. These revelations led to the study of KOR agonists as a potential treatment option in patients suffering from pruritic conditions. Pruritus associated with chronic kidney disease (also called uremic pruritus) affects 50-60% of all patients on dialysis and 25% of non-dialysis patients with chronic kidney disease. The clinical burden of uremic pruritus in this patient population is being increasingly recognized as contributing to a significant reduction in patient quality of life, poor outcomes, and even mortality. Options for therapy are limited - with no FDA-approved treatments, off-label [gabapentin] was the most evidence-based and widely available treatment. Difelikefalin received FDA approval in August 2021 (under the brand name Korsuva), becoming the first FDA-approved therapy for patients with chronic kidney disease suffering from uremic pruritus.

1 2D Structure

Difelikefalin

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

4-amino-1-[(2R)-6-amino-2-[[(2R)-2-[[(2R)-2-[[(2R)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid

2.1.2 InChI

InChI=1S/C36H53N7O6/c1-24(2)21-29(32(45)40-28(15-9-10-18-37)34(47)43-19-16-36(39,17-20-43)35(48)49)42-33(46)30(23-26-13-7-4-8-14-26)41-31(44)27(38)22-25-11-5-3-6-12-25/h3-8,11-14,24,27-30H,9-10,15-23,37-39H2,1-2H3,(H,40,45)(H,41,44)(H,42,46)(H,48,49)/t27-,28-,29-,30-/m1/s1

2.1.3 InChI Key

FWMNVWWHGCHHJJ-SKKKGAJSSA-N

2.1.4 Canonical SMILES

CC(C)CC(C(=O)NC(CCCCN)C(=O)N1CCC(CC1)(C(=O)O)N)NC(=O)C(CC2=CC=CC=C2)NC(=O)C(CC3=CC=CC=C3)N

2.1.5 Isomeric SMILES

CC(C)C[C@H](C(=O)N[C@H](CCCCN)C(=O)N1CCC(CC1)(C(=O)O)N)NC(=O)[C@@H](CC2=CC=CC=C2)NC(=O)[C@@H](CC3=CC=CC=C3)N

2.2 Other Identifiers

2.2.1 UNII

NA1U919MRO

2.3 Synonyms

2.3.1 MeSH Synonyms

1. 4-piperidinecarboxylic Acid, 4-amino-1-((2r)-6-amino-2-(((2r)-2-(((2r)-2-(((2r)-2-amino-1-oxo-3-phenylpropyl)amino)-1-oxo-3-phenylpropyl)amino)-4-methyl-1-oxopentyl)amino)-1-oxohexyl)-

2. Korsuva

3. N-((2r)-1-(((2r)-1-(((2r)-6-amino-1-(4-amino-4-carboxy-1-piperidinyl)-1-oxo-2-hexanyl)amino)-4-methyl-1-oxo-2-pentanyl)amino)-1-oxo-3-phenyl-2-propanyl)-d-phenylalaninamide

2.3.2 Depositor-Supplied Synonyms

1. 1024828-77-0

2. Cr845

3. Difelikefalin [inn]

4. Mr13a9

5. Cr-845

6. Korsuva

7. Fe202845

8. Na1u919mro

9. Fe-202845

10. Mr-13a9

11. 1024828-77-0 (free Base)

12. 1-(d-phenylalanyl-d-phenylalanyl-d-leucyl-d-lysyl)-4-aminopiperidine-4-carboxylic Acid

13. 4-piperidinecarboxylic Acid, N1-(d-phenylalanyl-d-phenylalanyl-d-leucyl-d-lysyl)-4-amino-

14. 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic Acid

15. Difelikefalin Acetate [jan]

16. Unii-na1u919mro

17. Kapruvia

18. Difelikefalin Tfa

19. Cr 845

20. Difelikefalin (cr845)

21. Difelikefalin (usan/inn)

22. Difelikefalin [usan:inn]

23. Difelikefalin [usan]

24. Seq Id No: 2

25. Difelikefalin [who-dd]

26. Gtpl9044

27. Chembl3989915

28. Schembl10316464

29. Bdbm235785

30. Dtxsid401032896

31. Bcp24752

32. Ex-a5855

33. At30197

34. Db11938

35. Bd177570

36. Hy-17609

37. Cr-845; Fe-202845

38. Cs-0014687

39. D11111

40. Us9359399, 2

41. Q21098992

42. D-phe-d-phe-d-leu-d-lys-[gamma-(4-n-piperidinyl)amino Carboxylic Acid]

43. 4-piperidinecarboylic Acid, 4-amino-1-(d-phenylalanyl-d-phenylalanyl-d-leucyl-d-lysyl)-

44. 4-amino-1-(d-phenylalanyl-d-phenylalanyl-d-leucyl-d-lysyl)piperidine-4-carboxylic Acid

45. 4-piperidinecarboxylic Acid, 4-amino-1-((2r)-6-amino-2-(((2r)-2-(((2r)-2-(((2r)-2-amino-1-oxo-3-phenylpropyl)amino)-1-oxo-3-phenylpropyl)amino)-4-methyl-1-oxopentyl)amino)-1-oxohexyl)-

46. N-((2r)-1-(((2r)-1-(((2r)-6-amino-1-(4-amino-4-carboxy-1-piperidinyl)-1-oxo-2-hexanyl)amino)-4-methyl-1-oxo-2-pentanyl)amino)-1-oxo-3-phenyl-2-propanyl)-d-phenylalaninamide

2.4 Create Date

2008-05-26

3 Chemical and Physical Properties

Molecular Formula	C₃₆H₅₃N₇O₆
Molecular Weight	679.8 g/mol
XLogP3	-0.6
Hydrogen Bond Donor Count	7
Hydrogen Bond Acceptor Count	9
Rotatable Bond Count	18
Exact Mass	679.40573244 g/mol
Monoisotopic Mass	679.40573244 g/mol
Topological Polar Surface Area	223 Å²
Heavy Atom Count	49
Formal Charge	0
Complexity	1080
Isotope Atom Count	0
Defined Atom Stereocenter Count	4
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

Difelikefalin is indicated for the treatment of moderate-to-severe pruritus associated with chronic kidney disease (CKD-aP; uremic pruritus) in adults undergoing hemodialysis.

FDA Label

Kapruvia is indicated for the treatment of moderate-to-severe pruritus associated with chronic kidney disease in adult patients on haemodialysis (see section 5. 1).

5 Pharmacology and Biochemistry

5.1 Pharmacology

Difelikefalin is administered to patients undergoing hemodialysis for chronic kidney disease (CKD) to prevent and treat the pruritus often associated with CKD. It is administered via bolus intravenous injection at the end of each hemodialysis treatment. As it works on opioid receptors, difelikefalin can cause dizziness, somnolence, and other CNS depressant effects that may impair mental or physical abilities - as such, patients should be advised to avoid operating dangerous machinery until the effect of difelikefalin on that patient is known.

5.2 ATC Code

V03AX

V - Various

V03 - All other therapeutic products

V03A - All other therapeutic products

V03AX - Other therapeutic products

V03AX04 - Difelikefalin

5.3 Absorption, Distribution and Excretion

Absorption

Difelikefalin is administered via bolus intravenous injection with each hemodialysis treatment - for this reason, each dose is effectively 100% bioavailable.

Route of Elimination

Following intravenous difelikefalin administration to hemodialysis patients, approximately 11% of the dose was excreted in the urine, 59% in the feces, and 20% in the dialysate.

Volume of Distribution

The mean volume of distribution of difelikefalin is approximately 238 mL/kg.

Clearance

One cycle of hemodialysis reduces difelikefalin plasma concentrations by 70-80% and no detectable drug remains after two cycles.

5.4 Metabolism/Metabolites

Difelikefalin is not metabolized to any appreciable extent and is not a substrate for cytochrome P450 enzymes.

5.5 Biological Half-Life

The half-life of difelikefalin in hemodialysis patients prior to dialysis ranges between 23 and 31 hours.

5.6 Mechanism of Action

Difelikefalin is a synthetic peptide and agonist of kappa opioid receptors (KORs), which have long been known to be involved with the itching sensation (in addition to playing some role in addiction). Endogenous KOR agonists - called dynorphins - have a neuroinhibitory effect on the itching sensation at the spinal cord level and mouse models have shown KOR agonist antipruritic activity when used to treat itching induced by different pruritogens. Although the specifics of the mechanism have yet to be elucidated, the administration of KOR agonists, like difelikefalin, in patients with uremic pruritus has proven an effective means to suppress scratching and improve their quality of life.