difelikefalin   Click here for help

GtoPdb Ligand ID: 9044

Synonyms: CR845 | D-Phe-D-Phe-D-Leu-D-Lys-[γ-(4-N-piperidinyl)amino carboxylic acid] | FE-202845 | Kapruvia® | Korsuva® | SEQ ID NO: 2 [6]
Approved drug Immunopharmacology Ligand
difelikefalin is an approved drug (FDA (2021), EMA (2022))
Compound class: Peptide or derivative
Comment: Difelikefalin is a first-in-class, peripherally acting, highly selective peptide agonist of the κ-opioid receptor, that was developed potential to treat chronic itch [4] and it is claimed in patent US7402564B1 [6]. This patent provides extensive results from preclinical testing, assessing the analgesic and anti-pruritic potential of difelikefalin.
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Ligand Activity Visualisation Charts

These are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts.

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View interactive charts of activity data across species
2D Structure
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2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

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SMILES / InChI / InChIKey
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SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

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Canonical SMILES NCCCCC(C(=O)N1CCC(CC1)(N)C(=O)O)NC(=O)C(NC(=O)C(NC(=O)C(Cc1ccccc1)N)Cc1ccccc1)CC(C)C
Isomeric SMILES NCCCC[C@H](C(=O)N1CCC(CC1)(N)C(=O)O)NC(=O)[C@H](NC(=O)[C@H](NC(=O)[C@@H](Cc1ccccc1)N)Cc1ccccc1)CC(C)C
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
InChI Key FWMNVWWHGCHHJJ-SKKKGAJSSA-N
No information available.
Summary of Clinical Use Click here for help
Difelikefalin (with research code CR845) was evaluated in Phase 3 clinical trial as an intravenous (i.v.) analgesic to treat post abdominal surgery pain (see NCT02542384). NCT02229929 (Phase 2) assessed i.v. CR845 in hemodialysis patients suffering from uremic pruritus [1] and NCT02524197 (Phase 2) investigated orally administered CR845 in patients with hip or knee osteoarthritis.
In August 2021, the FDA approved difelikefalin as a treatment for pateints with chronic kidney disease who develop hemodialysis-associated moderate-to-severe pruritus (uraemic itch) [5], based on efficacy data arising from the KALM-1 and KALM-2 clinical trials.
Mechanism Of Action and Pharmacodynamic Effects Click here for help
Difelikefalin is believed to activate κ receptors on peripheral nerve cells (thereby inhibiting afferent nerve activity and pain signalling) and on immune cells (inhibiting release of pro-inflammatory mediators such as cytokines and prostaglandins) [4].
Clinical Trials
Clinical Trial ID Title Type Source Comment References
NCT02229929 Safety and Pharmacokinetics of IV CR845 in Hemodialysis Patients, and Its Efficacy in Patients With Uremic Pruritus Phase 2 Interventional Cara Therapeutics, Inc.
NCT02524197 A Study of the Safety and Effectiveness of Orally Administered CR845 in Patients With Osteoarthritis of the Hip or Knee Phase 2 Interventional Cara Therapeutics, Inc.
NCT02542384 A Study Evaluating the Overall Pain Relief and Safety of Intravenous (IV) CR845 in Patients Undergoing Abdominal Surgery Phase 2/Phase 3 Interventional Cara Therapeutics, Inc.
NCT03636269 CR845-CLIN3103: A Global Study to Evaluate the Safety and Efficacy of CR845 in Hemodialysis Patients With Moderate-to-Severe Pruritus Phase 3 Interventional Cara Therapeutics, Inc. This study (KALM-2) was an international trial, whose results contributed to the FDA's first approval of difelikefalin. 3
NCT03422653 A Study to Evaluate the Safety and Efficacy of CR845 in Hemodialysis Patients With Moderate-to-Severe Pruritus (KALM-1) Phase 3 Interventional Cara Therapeutics, Inc. This study (KALM-1) was conducted in the United States, and its results were pivotal for difelikefalin's FDA approval. 2