Identification

Name
Icatibant
Accession Number
DB06196
Type
Small Molecule
Groups
Approved, Investigational
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
Product Ingredients
IngredientUNIICASInChI Key
Icatibant Acetate325O8467XK138614-30-9DKYJWPPYONLYTF-DZJWSCHMSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
FirazyrSolution10 mgSubcutaneousShire Orphan Therapies Inc2014-07-14Not applicableCanada
FirazyrInjection, solution30.0 mg/3mLSubcutaneousShire2011-08-25Not applicableUs
Categories
UNII
7PG89G35Q7
CAS number
130308-48-4
Weight
Average: 1304.522
Monoisotopic: 1303.660794719
Chemical Formula
C59H89N19O13S
InChI Key
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)[C@H](CO)NC(=O)[C@H](CC3=CC=CS3)NC(=O)CNC(=O)C3C[C@@H](O)CN3C(=O)C3CCCN3C(=O)C(CCCN=C(N)N)NC(=O)[C@H](N)CCCN=C(N)N)[C@@]1([H])CCCC2)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O

Pharmacology

Indication

Approved for use in acute attacks of hereditary angioedema (HAE). Investigated for use/treatment in angioedema, liver disease, and burns and burn infections.

Associated Conditions
Pharmacodynamics

Icatibant 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 action

Bradykinin 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.

TargetActionsOrganism
AB2 bradykinin receptor
antagonist
Human
UAminopeptidase N
inhibitor
Human
Absorption

The 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 binding
Not 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 elimination

Urine (<10% unchanged)

Half life

After subcutaneous administration, mean elimination half-life was 1.4 ± 0.4 hours.

Clearance

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

Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AbacavirAbacavir may decrease the excretion rate of Icatibant which could result in a higher serum level.
AcarboseAcarbose may decrease the excretion rate of Icatibant which could result in a higher serum level.
AceclofenacAceclofenac may decrease the excretion rate of Icatibant which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Icatibant which could result in a higher serum level.
AcetaminophenAcetaminophen may decrease the excretion rate of Icatibant which could result in a higher serum level.
Acetylsalicylic acidAcetylsalicylic acid may decrease the excretion rate of Icatibant which could result in a higher serum level.
AclidiniumIcatibant may decrease the excretion rate of Aclidinium which could result in a higher serum level.
AcrivastineIcatibant may decrease the excretion rate of Acrivastine which could result in a higher serum level.
AcyclovirAcyclovir may decrease the excretion rate of Icatibant which could result in a higher serum level.
AdefovirAdefovir may decrease the excretion rate of Icatibant which could result in a higher serum level.
Food Interactions
Not Available

References

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
Human Metabolome Database
HMDB0015624
KEGG Drug
D04492
PubChem Compound
71364
PubChem Substance
99443237
ChemSpider
64461
BindingDB
50142947
ChEBI
68564
ChEMBL
CHEMBL2028850
Therapeutic Targets Database
DCL000131
PharmGKB
PA164749185
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Icatibant
ATC Codes
B06AC02 — Icatibant
AHFS Codes
  • 92:32.00 — Complement Inhibitors
FDA label
Download (543 KB)
MSDS
Download (87.6 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentHereditary Angioedema (HAE)1
1TerminatedTreatmentAngioneurotic Edema1
2Active Not RecruitingPreventionHemodialysis-Induced Symptom / Mitochondrial Diseases1
2CompletedTreatmentAngioedema1
2WithdrawnBasic ScienceChronic heart failure with reduced ejection fraction (NYHA Class II) / Chronic heart failure with reduced ejection fraction (NYHA Class III) / NYHA Class I Congestive heart failure1
2, 3CompletedPreventionCardiopulmonary Bypass / Fibrinolysis / General Surgery / Inflammatory Reaction1
3CompletedTreatmentAngioedema1
3CompletedTreatmentAngiotensin Converting Enzyme Inhibitor Induced Angioedema1
3CompletedTreatmentHereditary Angioedema3
3CompletedTreatmentHereditary Angioedema / Hereditary Angioedema (HAE)1
4CompletedTreatmentHereditary Angioedema1
4TerminatedTreatmentACE Inhibitor-associated Angioedema1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, solutionSubcutaneous30.0 mg/3mL
SolutionSubcutaneous10 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US5648333No1999-07-152019-07-15Us

Properties

State
Solid
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 FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
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)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as oligopeptides. These are organic compounds containing a sequence of between three and ten alpha-amino acids joined by peptide bonds.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Amino acids, peptides, and analogues
Direct Parent
Oligopeptides
Alternative Parents
N-acyl-L-alpha-amino acids / Proline and derivatives / Alpha amino acid amides / Tetrahydroisoquinolines / Indoles and derivatives / N-acylpyrrolidines / Pyrrolidinecarboxamides / Benzenoids / N-acyl amines / Thiophenes
show 17 more
Substituents
Alpha-oligopeptide / Proline or derivatives / N-acyl-alpha-amino acid / N-acyl-alpha amino acid or derivatives / N-acyl-l-alpha-amino acid / Alpha-amino acid amide / N-substituted-alpha-amino acid / Alpha-amino acid or derivatives / Tetrahydroisoquinoline / Indole or derivatives
show 38 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not 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
Uniprot Name
B2 bradykinin receptor
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 pathogen...
Gene Name
ANPEP
Uniprot ID
P15144
Uniprot Name
Aminopeptidase N
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]

Drug created on March 19, 2008 10:16 / Updated on November 12, 2018 07:31