kappa opioid receptor (KOR)
Kappa opioid receptor (KOR). Difelikefalin is a selective and peripherally restricted agonist of KOR.

Difelikefalin (CR-845; FE-202845) does not penetrate the blood-brain barrier. Difelikefalin does not bind to any receptors other than KORs, including mu opioid receptors[1].

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Difelikefalin is a selective KOR agonist that produces anti-inflammatory effects. KOR agonists work to inhibit the itching sensation at the spinal cord level. The compound demonstrates high selectivity for KOR over other opioid receptors.

Difelikefalin modulates pruritus in conditions such as chronic kidney disease. It produces anti-inflammatory effects and has demonstrated efficacy in reducing itching in patients with chronic kidney disease undergoing hemodialysis. Clinical trials showed significant improvement in pruritus symptoms in this patient population.

In vitro receptor binding assays for difelikefalin evaluate its affinity and selectivity for the kappa opioid receptor (KOR) versus mu and delta opioid receptors. Radioligand binding studies using membranes from cells expressing recombinant opioid receptors and radiolabeled selective KOR ligands are conducted to determine binding affinity (Ki) and selectivity ratios.

In vitro cell-based functional assays for difelikefalin evaluate its agonist activity at KOR using assays such as GTPγS binding, cAMP accumulation inhibition, or β-arrestin recruitment. Cells expressing recombinant KOR are treated with the compound, and receptor activation is measured. The compound's peripheral restriction can be confirmed using permeability assays.

In vivo animal studies for difelikefalin have been conducted in various models of pruritus. Compound is administered systemically (e.g., intravenously or subcutaneously), and scratching behavior is measured as the primary endpoint. Pharmacodynamic markers of KOR activation are also assessed. These studies supported the compound's advancement into clinical trials and subsequent FDA approval.

Absorption, Distribution and Excretion
Defecalin is administered via intravenous bolus injection with each hemodialysis session—therefore, the bioavailability of each dose is almost 100%. After intravenous injection, approximately 11% of the dose is excreted in the urine, 59% in the feces, and 20% in the dialysate. The mean volume of distribution of defecalin is approximately 238 mL/kg. A single hemodialysis cycle can reduce defecalin plasma concentration by 70-80%, and drug residues are undetectable after two cycles. Metabolism/Metabolites Defecalin is hardly metabolized and is not a substrate for cytochrome P450 enzymes. Biological Half-Life Before dialysis, the half-life of metformin in hemodialysis patients is 23 to 31 hours.

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Difelikefalin is a peripherally restricted compound that does not cross the blood-brain barrier, minimizing central nervous system side effects associated with opioid receptor activation. It has a molecular weight of 679.8 g/mol. The compound is administered intravenously. Detailed pharmacokinetic parameters such as half-life and clearance are established in the approved product labeling.

Protein Binding
Difelikefalin is approximately 23-28% bound to proteins in plasma, although it is unclear which specific proteins it binds to.

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Difelikefalin has not been associated with serum enzyme elevations during therapy or with episodes of clinically apparent liver injury. As a peripherally restricted KOR agonist, it avoids central nervous system side effects such as sedation, euphoria, and dependence. Common side effects include diarrhea, nausea, dizziness, and headache. The compound is FDA-approved for its indicated use.

[1]. Randomized Controlled Trial of Difelikefalin for Chronic Pruritus in Hemodialysis Patients. Kidney Int Rep. 2020 Jan 28;5(5):600-610.

[2]. A Phase 3 Trial of Difelikefalin in Hemodialysis Patients With Pruritus. N Engl J Med. 2020 Jan 16;382(3):222-232.

Defecafalin (CR845) is a κ-opioid receptor (KOR) agonist used to treat pruritus secondary to chronic kidney disease (CKD). The association between KOR and pruritus was first discovered in 1984. Further research showed that the endogenous KOR agonist dynorphin could suppress pruritus at the spinal cord level, and that in mouse models, administration of KOR antagonists could induce scratching behavior. These findings prompted investigations into KOR agonists as a potential treatment for patients with pruritus. CKD-related pruritus (also known as uremic pruritus) affects 50-60% of dialysis patients and 25% of non-dialysis CKD patients. The clinical burden of uremic pruritus on these patients is increasingly recognized, as it leads to significantly reduced quality of life, poor prognosis, and even death. Treatment options are limited—due to the lack of FDA-approved therapies, off-label use [gabapentin] is the most well-supported and widely used treatment. Definalifarin was approved by the FDA in August 2021 (brand name Korsuva), becoming the first FDA-approved therapy for the treatment of pruritus associated with uremic syndrome in patients with chronic kidney disease. Definalifarin was subsequently approved by the EMA in April 2022 for the same indication. Definalifarin is a κ-opioid receptor agonist. Its mechanism of action is as an opioid κ-receptor agonist. See also: Definalifarin acetate (active ingredient).

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Drug Indications
Definalifarin 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
Korsuva is indicated for the treatment of moderate to severe pruritus in adults with chronic kidney disease undergoing hemodialysis (see Section 5.1).
Treatment of Chronic Kidney Disease-Related Pruritus
Mechanism of Action

Defenfalin is a synthetic peptide and an agonist of the κ-opioid receptor (KOR), which has long been known to be associated with pruritus (and also plays a role in addiction). Endogenous κ-opioid receptor agonists (called dynorphins) have a neuroinhibitory effect on pruritus sensation at the spinal cord level, and mouse models have demonstrated their antipruritic activity in treating pruritus induced by various pruritogens. Although the specific mechanism is not fully elucidated, the use of κ-opioid receptor agonists (such as defenfalin) has proven to be an effective way to inhibit scratching and improve the quality of life for patients with uremic pruritus.
Pharmacodynamics

Defenfalin is used to treat hemodialysis patients with chronic kidney disease (CKD) to prevent and treat pruritus, a common CKD symptom. It is administered via intravenous bolus at the end of each hemodialysis session. Because defecallifalin acts on opioid receptors, it can cause dizziness, drowsiness, and other central nervous system depressant effects, thereby impairing mental or physical abilities—therefore, patients should be advised to avoid operating dangerous machinery until they understand the effects of defecallifalin on them.

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Difelikefalin (CR845, Korsuva®) is a synthetic all-D-amino acid tetrapeptide and highly selective peripherally restricted KOR agonist. It received FDA approval in August 2021 for pruritus associated with chronic kidney disease in hemodialysis patients, becoming the first FDA-approved therapy for this indication. EMA approval followed in April 2022. The compound modulates pruritus through KOR activation and has anti-inflammatory effects. It is not associated with liver injury.

C36H53N7O6

679.86

679.406

C, 63.60; H, 7.86; N, 14.42; O, 14.12

1024828-77-0

413256-25-2 (1HCl); 1024829-44-4 (acetate); 1024828-77-0; 2711717-77-8 (3HCl); 2742623-88-5 (TFA)

24794466

White to off-white solid powder

4.044

7

9

18

49

1080

4

O([H])C(C1(C([H])([H])C([H])([H])N(C([C@@]([H])(C([H])([H])C([H])([H])C([H])([H])C([H])([H])N([H])[H])N([H])C([C@@]([H])(C([H])([H])C([H])(C([H])([H])[H])C([H])([H])[H])N([H])C([C@@]([H])(C([H])([H])C2C([H])=C([H])C([H])=C([H])C=2[H])N([H])C([C@@]([H])(C([H])([H])C2C([H])=C([H])C([H])=C([H])C=2[H])N([H])[H])=O)=O)=O)=O)C([H])([H])C1([H])[H])N([H])[H])=O

FWMNVWWHGCHHJJ-SKKKGAJSSA-N

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

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

MR-13A9; CR-845; MR-13A-9; MR13A9; CR845; MR13A-9; trade name Korsuva

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: ~100 mg/mL (~147.1 mM)
H2O: ≥ 100 mg/mL (~147.1 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (3.68 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (3.68 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (3.68 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)