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New Drug Approvals 2011 - Pt. XXVI - Icatibant (FirazyrTM)






ATCC: C01EB19
Wikipedia: Icatibant

On the August 25th 2011, the FDA approved Icatibant (trade name: FirazyrTM), a bradykinin B2 receptor (B2R) antagonist indicated for the treatment of acute attacks of hereditary angioedema (HAE) in patients aged 18 or older.


HAE is a rare genetic disease and is caused by low levels of C1-esterase inhibitor (C1-INH), the major endogenous inhibitor and regulator of the protease plasma kallikrein and the key regulator of the Factor XII/kallikrein cascade. One component this cascade is the production of bradykinin by plasma kallikrein. During HAE attacks, disregulated activity of plasma kallikrein leads to excessive bradykinin production; bradykinin is a potent vasodilator, which s thought to be responsible for the characteristic HAE symptoms of localised swelling, inflammation and pain.

Icatibant treats the clinical symptoms of HAE attack by selective- and competitively binding, as an antagonist, to the B2 bradykinin receptor (B2R) (Uniprot: P30411; ChEMBL ID: CHEMBL3157; PFAM: PF00001), with similar affinity to bradykinin (1-10 nM for the B2R, while affinity for the B1R is 100-fold lower). Icatibant is the first in class agent against this target. The -tibant stem covers bradykinin antagonists.


B2R is a Rhodopsin-like receptor, 391 amino acid long, which belongs to the G protein-coupled receptor (GPCR) A3 family and is encoded by the BDKRB2 gene in humans. The amino acid sequence of B2R is:

>B2R 
MFSPWKISMFLSVREDSVPTTASFSADMLNVTLQGPTLNGTFAQSKCPQVEWLGWLNTIQ
PPFLWVLFVLATLENIFVLSVFCLHKSSCTVAEIYLGNLAAADLILACGLPFWAITISNN
FDWLFGETLCRVVNAIISMNLYSSICFLMLVSIDRYLALVKTMSMGRMRGVRWAKLYSLV
IWGCTLLLSSPMLVFRTMKEYSDEGHNVTACVISYPSLIWEVFTNMLLNVVGFLLPLSVI
TFCTMQIMQVLRNNEMQKFKEIQTERRATVLVLVVLLLFIICWLPFQISTFLDTLHRLGI
LSSCQDERIIDVITQIASFMAYSNSCLNPLVYVIVGKRFRKKSWEVYQGVCQKGGCRSEP
IQMENSMGTLRTSISVERQIHKLQDWAGSRQ
There are no known experimental structures of B2R, however there are several relevant homologous structures of other members of the rhodopsin-like GPCR family (see here for a current list).
Icatibant is the third drug approved in the US to treat HAE attacks. Previous drugs include Ecallantide (approved in December 2009 under the trade name Kalbitor), which is a potent, selective, reversible inhibitor of plasma kallikrein, and C1-INH (approved in October 2009 under the trade name Berinert), which is a freeze-dried human C1-esterase inhibitor concentrate.

Icatibant (IUPAC: (2S)-2-[[(3aS,7aS)-1-[2-[(2S)-2-[[(2S)-2-[[2-[[(4R)-1-[1-[2-[[(2R)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]-4-hydroxypyrrolidine-2-carbonyl]amino]acetyl]amino]-3-thiophen-2-ylpropanoyl]amino]-3-hydroxypropanoyl]-3,4-dihydro-1H-isoquinoline-3-carbonyl]-2,3,3a,4,5,6,7,7a-octahydroindole-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoic acid; ChEMBL ID: CHEMBL375218; PubChem: 71364; ChemSpider: 5293384) is a synthetic decapeptide that differs from bradykinin (a nonapeptide with an amino acid sequence RPPGFSPFR) at the amino acids' positions 3, 5, 7 and 8, which have been replaced by four non-natural amino acids, and also in one additional amino acid (a D-arginine) at the N-terminus of the bradykinin arginine at position 1. Thus, Icatibant amino acid sequence is D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg. These modifications prevent Icatibant from being metabolised by major bradykinin-metabolizing enzymes, which makes it more stable that bradykinin. Icatibant has a molecular weight of 1304.5 Da.

Icatibant can be self-administrated through an injection in the abdominal area, thus providing a new option for the treatment of acute HAE attacks. The recommended dose is 30 mg administrated subcutaneously. In the case of inadequate response or recurrence of symptoms, additional dose may be administrated at intervals of at least 6 hours, with no more than 3 doses administrated in any 24-hour period (recommended daily dose equivalent 69.0 umol). 

Following a 30 mg subcutaneous dose, the absolute bioavailability of Icatibant is ca. 97%, with a plasma clearance of 245 mL/min, a mean elimination half-life of 1.4 hours and a volume of distribution of 29 L. Icatibant is extensively metabolised by proteolytic enzymes to inactive metabolites that are primarily excreted in the urine, with <10% of the dose eliminated as unchanged drug. As would be anticipated for a peptide drug, Icatibant is not an inhibitor of major cytochrome P450 (CYP) isoenzymes and is not an inducer of CYP 1A2 and 3A4.


The full prescribing information can be found here.


Icatibant is marketed by Shire Human Genetic Therapies Inc. and the product website is www.firazyr.com (Since 2008, Icatibant has been approved for use in the European Union; the european SPC can be found here).

Comments

Unknown said…
First of all I've got to say I'm really enjoying this new series of drug approval posts.

With regards to the links in this post. I believe that the structure that you've shown is the same as as that described in Shire's literature:
http://pi.shirecontent.com/PI/PDFs/Firazyr_USA_ENG.pdf

But would argue that none of the other sources accurately describe the structure.

The PubChem record has 5 undefined stereocentres (based on the image and the InChI displayed on the page)
http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=71364&loc=ec_rcs

The CHEMBL record has 2 undefined stereocentres.

https://www.ebi.ac.uk/chembldb/compound/inspect/CHEMBL375218

Sadly, the ChemSpider record that was associated with the name Icatibant (previously - 16736634) was also missing a stereocentre. But on the basis looking at the structure that you provided in the blog post and the Shire documentation I have curated the database to make ChemSpider record http://www.chemspider.com/Chemical-Structure.5293384.html the record for Icatibant.
Shaun said…
Hi Dave,

This compound was redrawn last week after we noticed that the stereocentres were missing. It should be loaded for the next release. thanks,
Louisa (ChEMBL chemical curator)

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