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Identification
NameIcatibant
Accession NumberDB06196
TypeSmall Molecule
GroupsApproved
Description

Icatibant (Firazyr) is a synthetic peptidomimetic drug consisting of ten amino acids, and acts as an effective and specific antagonist of bradykinin B2 receptors. It has been approved in the EU for use in hereditary angioedema, and is under investigation for a number of other conditions in which bradykinin is thought to play a significant role. Icatibant currently has orphan drug status in the United States and FDA approved on August 25, 2011.

Structure
Thumb
Synonyms
HOE 140
External Identifiers Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Firazyrinjection, solution30 mg/3mLsubcutaneousShire US Manufacturing Inc.2011-08-25Not applicableUs
Firazyrsolution10 mgsubcutaneousShire Orphan Therapies Inc2014-07-14Not applicableCanada
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Icatibant Acetate
Thumb
  • InChI Key: DKYJWPPYONLYTF-DZJWSCHMSA-N
  • Monoisotopic Mass: 1362.697908506
  • Average Mass: 1363.59
DBSALT000097
Categories
UNII7PG89G35Q7
CAS number130308-48-4
WeightAverage: 1304.522
Monoisotopic: 1303.660794719
Chemical FormulaC59H89N19O13S
InChI KeyInChIKey=QURWXBZNHXJZBE-MCDGZUPGSA-N
InChI
InChI=1S/C59H89N19O13S/c60-37(14-5-19-67-57(61)62)48(82)72-38(15-6-20-68-58(63)64)52(86)75-22-8-18-43(75)54(88)77-30-35(80)26-44(77)50(84)70-28-47(81)71-40(27-36-13-9-23-92-36)49(83)74-41(31-79)53(87)76-29-34-12-2-1-10-32(34)24-46(76)55(89)78-42-17-4-3-11-33(42)25-45(78)51(85)73-39(56(90)91)16-7-21-69-59(65)66/h1-2,9-10,12-13,23,33,35,37-46,79-80H,3-8,11,14-22,24-31,60H2,(H,70,84)(H,71,81)(H,72,82)(H,73,85)(H,74,83)(H,90,91)(H4,61,62,67)(H4,63,64,68)(H4,65,66,69)/t33-,35+,37+,38?,39-,40-,41-,42-,43?,44?,45?,46?/m0/s1
IUPAC Name
(2S)-2-{[(3aS,7aS)-1-{2-[(2S)-2-[(2S)-2-(2-{[(4R)-1-(1-{2-[(2R)-2-amino-5-[(diaminomethylidene)amino]pentanamido]-5-[(diaminomethylidene)amino]pentanoyl}pyrrolidine-2-carbonyl)-4-hydroxypyrrolidin-2-yl]formamido}acetamido)-3-(thiophen-2-yl)propanamido]-3-hydroxypropanoyl]-1,2,3,4-tetrahydroisoquinoline-3-carbonyl}-octahydro-1H-indol-2-yl]formamido}-5-[(diaminomethylidene)amino]pentanoic acid
SMILES
[H][C@]12CC(N(C(=O)C3CC4=CC=CC=C4CN3C(=O)[[email protected]](CO)NC(=O)[[email protected]](CC3=CC=CS3)NC(=O)CNC(=O)C3C[C@@H](O)CN3C(=O)C3CCCN3C(=O)C(CCCN=C(N)N)NC(=O)[[email protected]](N)CCCN=C(N)N)[C@@]1([H])CCCC2)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as polypeptides. These are peptides containing ten or more amino acid residues.
KingdomOrganic compounds
Super ClassOrganic Polymers
ClassPolypeptides
Sub ClassNot Available
Direct ParentPolypeptides
Alternative Parents
Substituents
  • Polypeptide
  • Alpha peptide
  • N-acyl-aliphatic-alpha amino acid
  • N-acyl-alpha amino acid or derivatives
  • N-acyl-alpha-amino acid
  • Alpha-amino acid amide
  • N-acyl-l-alpha-amino acid
  • Tetrahydroisoquinoline
  • Alpha-amino acid or derivatives
  • N-substituted-alpha-amino acid
  • Indole or derivatives
  • Pyrrolidine-2-carboxamide
  • Pyrrolidine carboxylic acid or derivatives
  • N-acylpyrrolidine
  • Amino fatty acid
  • Fatty acyl
  • Benzenoid
  • N-acyl-amine
  • Fatty amide
  • Heteroaromatic compound
  • Thiophene
  • Tertiary carboxylic acid amide
  • Pyrrolidine
  • Tertiary amine
  • Secondary carboxylic acid amide
  • Secondary alcohol
  • Guanidine
  • Carboxamide group
  • Azacycle
  • Organoheterocyclic compound
  • Organic 1,3-dipolar compound
  • Propargyl-type 1,3-dipolar organic compound
  • Carboximidamide
  • Monocarboxylic acid or derivatives
  • Carboxylic acid
  • Carboxylic acid derivative
  • Carboxylic acid amide
  • Hydrocarbon derivative
  • Primary amine
  • Primary alcohol
  • Organooxygen compound
  • Organonitrogen compound
  • Primary aliphatic amine
  • Carbonyl group
  • Amine
  • Alcohol
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External DescriptorsNot Available
Pharmacology
IndicationApproved for use in acute attacks of hereditary angioedema (HAE). Investigated for use/treatment in angioedema, liver disease, and burns and burn infections.
PharmacodynamicsIcatibant is a potent, specific, competitive, and selective peptidomimetic bradykinin beta2-receptor antagonist (pA2 = 9.04). It has a modified peptide structure, and is the first bradykinin receptor antagonist to act on the guinea-pig trachea without demonstrating agonist effects. It also inhibits aminopeptidase N (Ki = 9.1 μM). If an IV dose of 0.4 and 0.8 mg/kg was infused over 4 hours, one may observe an inhibited response to bradykinin challenge for 6 - 8 hours following completion of infusion.
Mechanism of actionBradykinin is a peptide-based hormone that is formed locally in tissues, very often in response to a trauma. It increases vessel permeability, dilates blood vessels and causes smooth muscle cells to contract. Bradykinin plays an important role in the mediation of pain. Surplus bradykinin is responsible for the typical symptoms of inflammation, such as swelling, redness, overheating and pain. These symptoms are mediated by activation of bradykinin B2 receptors. In patients with HAE, they have an absent or dysfunctional C1-esterase inhibitor. This inhibitor is responsible for the production of bradykinin in which displacement of bradykinin from B2 receptors by icatibant has an inhibitory effect on the receptor for a relatively long time.
Related Articles
AbsorptionThe absolute bioavailability of icatibant following a 30 mg subcutaneous dose is approximately 97%. Maximum plasma concentrations (Cmax) of 974 ± 280 ng/mL was reached when a single subcutaneous dose of 30 mg was administered. The AUC was 2165 ± 568 ng∙hr/mL. Icatibant did not accumulate following multiple doses.
Volume of distribution

Vdss, subcutaneous injection = 29.0 ± 8.7 L.

Protein bindingNot Available
Metabolism

Icatibant is metabolized by proteolytic enzymes into inactive metabolites. The cytochrome P450 enzyme system is not involved with the metabolism of icatibant.

Route of eliminationUrine (<10% unchanged)
Half lifeAfter subcutaneous administration, mean elimination half-life was 1.4 ± 0.4 hours.
Clearance

Plasma clearance following subcutaneous administration was 245 ± 58 mL/min.

ToxicityNot Available
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.5123
Blood Brain Barrier-0.8713
Caco-2 permeable-0.8198
P-glycoprotein substrateSubstrate0.8421
P-glycoprotein inhibitor INon-inhibitor0.8961
P-glycoprotein inhibitor IINon-inhibitor0.9801
Renal organic cation transporterNon-inhibitor0.6176
CYP450 2C9 substrateNon-substrate0.7753
CYP450 2D6 substrateNon-substrate0.7828
CYP450 3A4 substrateNon-substrate0.5958
CYP450 1A2 substrateNon-inhibitor0.661
CYP450 2C9 inhibitorNon-inhibitor0.8477
CYP450 2D6 inhibitorNon-inhibitor0.876
CYP450 2C19 inhibitorNon-inhibitor0.796
CYP450 3A4 inhibitorNon-inhibitor0.729
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9691
Ames testNon AMES toxic0.6483
CarcinogenicityNon-carcinogens0.8963
BiodegradationNot ready biodegradable0.898
Rat acute toxicity2.4262 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9506
hERG inhibition (predictor II)Inhibitor0.5187
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
Injection, solutionsubcutaneous30 mg/3mL
Solutionsubcutaneous10 mg
PricesNot Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US5648333 No1999-07-152019-07-15Us
Properties
StateSolid
Experimental Properties
PropertyValueSource
water solubility1 mg/mL MSDS
Predicted Properties
PropertyValueSource
Water Solubility0.057 mg/mLALOGPS
logP-2.3ALOGPS
logP-8ChemAxon
logS-4.4ALOGPS
pKa (Strongest Acidic)3.46ChemAxon
pKa (Strongest Basic)11.45ChemAxon
Physiological Charge3ChemAxon
Hydrogen Acceptor Count23ChemAxon
Hydrogen Donor Count15ChemAxon
Polar Surface Area523.72 Å2ChemAxon
Rotatable Bond Count30ChemAxon
Refractivity332.91 m3·mol-1ChemAxon
Polarizability137.03 Å3ChemAxon
Number of Rings7ChemAxon
Bioavailability0ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis ReferenceNot Available
General References
  1. Cockcroft JR, Chowienczyk PJ, Brett SE, Bender N, Ritter JM: Inhibition of bradykinin-induced vasodilation in human forearm vasculature by icatibant, a potent B2-receptor antagonist. Br J Clin Pharmacol. 1994 Oct;38(4):317-21. [PubMed:7833220 ]
  2. Bork K, Frank J, Grundt B, Schlattmann P, Nussberger J, Kreuz W: Treatment of acute edema attacks in hereditary angioedema with a bradykinin receptor-2 antagonist (Icatibant). J Allergy Clin Immunol. 2007 Jun;119(6):1497-503. Epub 2007 Apr 5. [PubMed:17418383 ]
External Links
ATC CodesB06AC02
AHFS Codes
  • 92:32
PDB EntriesNot Available
FDA labelDownload (543 KB)
MSDSDownload (87.6 KB)
Interactions
Drug Interactions
Drug
BenazeprilIcatibant may decrease the antihypertensive activities of Benazepril.
CaptoprilIcatibant may decrease the antihypertensive activities of Captopril.
CilazaprilIcatibant may decrease the antihypertensive activities of Cilazapril.
EnalaprilIcatibant may decrease the antihypertensive activities of Enalapril.
EnalaprilatIcatibant may decrease the antihypertensive activities of Enalaprilat.
FosinoprilIcatibant may decrease the antihypertensive activities of Fosinopril.
LisinoprilIcatibant may decrease the antihypertensive activities of Lisinopril.
MoexiprilIcatibant may decrease the antihypertensive activities of Moexipril.
PerindoprilIcatibant may decrease the antihypertensive activities of Perindopril.
QuinaprilIcatibant may decrease the antihypertensive activities of Quinapril.
RamiprilIcatibant may decrease the antihypertensive activities of Ramipril.
TrandolaprilIcatibant may decrease the antihypertensive activities of Trandolapril.
Food InteractionsNot Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
antagonist
General Function:
Type 1 angiotensin receptor binding
Specific Function:
Receptor for bradykinin. It is associated with G proteins that activate a phosphatidylinositol-calcium second messenger system.
Gene Name:
BDKRB2
Uniprot ID:
P30411
Molecular Weight:
44460.15 Da
References
  1. Privitera PJ, Beckstead RM, Yates P, Walgren R: Autoradiographic localization of [125I-Tyr0]bradykinin binding sites in brains of Wistar-Kyoto and spontaneously hypertensive rats. Cell Mol Neurobiol. 2003 Oct;23(4-5):805-15. [PubMed:14514033 ]
  2. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Zinc ion binding
Specific Function:
Broad specificity aminopeptidase. Plays a role in the final digestion of peptides generated from hydrolysis of proteins by gastric and pancreatic proteases. May play a critical role in the pathogenesis of cholesterol gallstone disease. May be involved in the metabolism of regulatory peptides of diverse cell types, responsible for the processing of peptide hormones, such as angiotensin III and I...
Gene Name:
ANPEP
Uniprot ID:
P15144
Molecular Weight:
109538.68 Da
References
  1. Bawolak MT, Fortin JP, Vogel LK, Adam A, Marceau F: The bradykinin B2 receptor antagonist icatibant (Hoe 140) blocks aminopeptidase N at micromolar concentrations: off-target alterations of signaling mediated by the bradykinin B1 and angiotensin receptors. Eur J Pharmacol. 2006 Dec 3;551(1-3):108-11. Epub 2006 Sep 8. [PubMed:17026984 ]
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Drug created on March 19, 2008 10:16 / Updated on May 25, 2016 02:16