Icatibant
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Icatibant (Firazyr)
Effective Against
Icatibant, a synthetic peptidomimetic, works by blocking the B2 receptor as an antagonist to the peptide hormone bradykinin.
Cost
From Sigma-Aldrich: 163 USD (250ug)
From Tocris Bioscience: 141 USD (500 ug)
Reported Route of Synthesis
Icatibant can be chemically synthesized by standard solid-phase methodology on a 430A peptide synthesizer. Esterification of Fmoc-L-arginine (I) with Wang resin affords the esterified resin (II) by the modified Fmoc method. The segment is previously deblocked with Pip and then couples as a sequence with alfa-Fmoc-aminoacids (activated with HOOBt and DIC (1) or HOBt and DCC (2) in DMF/NMP (1)) which are always N-deprotected in the presence of Pip in DMF prior to the next coupling. After the completion of the reaction, peptide is split off from the resin and deprotected of the side chain groups using EDT, PhSCH3 and TFA (1,2) in C6H5OH/H2O (2) to furnish the free base of the title compound (1,2).
Kennedy, K.J.; Orwig, K.S.; Dix, T.A.; Christopher, J.; Jaffa, A.A. Synthesis and analysis of potent, more lipophilic derivatives of the bradykinin B2 receptor antagonist peptide Hoe 140 J Pept Res 2002, 59(4): 139
sanofi-aventis Deutschland GmbH. Peptides having bradykinin antagonist action DE 3938751, US 5648333
Cost of Intermediates:
D-Arginine from Sigma-Aldrich (D-Arg): 185 USD (5g)
L-Arginine from Sigma-Aldrich (Arg): 51.4 USD (100g)
L-Proline from Sigma-Aldrich (Pro): 101.5 USd (100g)
Trans-4-Hydroxy-L-proline from Sigma-Aldrich (Hyp): 532 USD (100g)
Glycine from Sigma-Aldrich (Gly): 61.60 USD (250g)
Fmoc -β-(2-Thienyl)-L-alanine from Anaspec (Thi): 320 USD (5g)
L-Serine from Sigma-Aldrich (Ser): 100 USD (100g)
Boc-D-Tic-OH from Sigma-Aldrich (Tic): 180 USD (1g)
L-Octahydroindole-2-carboxylic acid from BACHEM (Oic): 1,145 USD (5g)
"Icatibant is synthesised in a solid phase peptide synthesis (SPPS) process. It is synthesized from the appropriate protected L- and D-amino acids and protected glycine. The suitable coupling and cleavage methods have been selected to minimize isomerisation of both starting materials and the growing peptide chain. A detailed description of the manufacturing process including process flow diagram and in process controls was provided in the restricted part of the Active Substance Master File (ASMF)."
European Public Assessment Report on Firazyr, Scientific Discussion, accessed 7/2/2009
If PDF doesn't show, try the following website http://www.emea.europa.eu/humandocs/Humans/EPAR/firazyr/firazyr.htm
"Firazyr is a formulation of a incatibant acetate, an acetate salt of a fully synthetic decapeptide with a structure similar to bradykinin, but with 5 nonproteinogenic amino acids. It consists of ten amino acids in the following sequence: H-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH. All the chiral amino acids of icatibant are in the L-configuration with the exception of arginine (position 1) and 1, 2, 3, 4-tetrahydroisoquinoline-3-carboxylic acid (position 8). "
Biotechnology Information Institute - 663 Icatibant
Sorbera, L.A., Fernandez-Forner, D., Bayes, M. Icatibant Acetate. Drugs of the Future 31(2):101