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    Difelikefalin

    ACTIVE PHARMA INGREDIENTS

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    2D Structure
    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

    2D Structure

    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 Weight 679.8 g/mol
    Molecular Formula C36H53N7O6
    XLogP3-0.6
    Hydrogen Bond Donor Count7
    Hydrogen Bond Acceptor Count9
    Rotatable Bond Count18
    Exact Mass679.40573244 g/mol
    Monoisotopic Mass679.40573244 g/mol
    Topological Polar Surface Area223 Ų
    Heavy Atom Count49
    Formal Charge0
    Complexity1080
    Isotope Atom Count0
    Defined Atom Stereocenter Count4
    Undefined Atom Stereocenter Count0
    Defined Bond Stereocenter Count0
    Undefined Bond Stereocenter Count0
    Covalently Bonded Unit Count1
    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.