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Chemical Compound Review

Firazyr     (2S)-2-[[(3aS,7aS)-1-[[2- [(2S)-2-[[(2S)-2...

Synonyms: Icatibant, Hoe-140, HOE140, CHEMBL411169, AG-D-78043, ...
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Disease relevance of Icatibant


High impact information on Icatibant

  • The antiischemic effect of ACE inhibitors and BK were abolished by the addition of L-NNA (1 x 10(-6) mol/l) or icatibant (1 x 10(-9) mol/l) [1].
  • Removal of endothelium or treatment with icatibant and L-NAME abolished these AT2-mediated effects [5].
  • Two months after MI, rats were treated for 2 mo with: (a) vehicle; (b) the ACEi ramipril, with and without the B2 receptor antagonist icatibant (B2-ant); or (c) an AT1-ant with and without an AT2-antagonist (AT2-ant) or B2-ant [6].
  • Chronic blockade of B2-receptors by Icatibant (50 nmol/100 g body wt twice a day S.C.) or inhibition of nitric oxide synthase by nitro-L-arginine-methyl ester (0.14 mmol/100 g body wt orally) increased the blood pressure of Bk2r+/+ to the levels of Bk2r-/- mice [7].
  • METHODS AND RESULTS: Rats underwent coronary artery ligation followed by chronic B2 kinin receptor blockade with icatibant [8].

Chemical compound and disease context of Icatibant


Biological context of Icatibant

  • The recombinantly expressed chicken receptor had IC50 values of 4.7 nM for the authentic ligand, ornithokinin ([Thr6,Leu8]bradykinin), 3.8 nM for HOE140, and >/=10 microM for bradykinin, [des-Arg9]bradykinin, and [des-Arg9,Leu8]bradykinin [13].
  • Our results provide direct biochemical evidence that the binding site for the agonist BK in the bovine B2 receptor is adjacent to a cysteine and is differentiated from the binding site(s) for the antagonists NPC17731 and HOE140 [14].
  • The protective effect of kallikrein on apoptosis and its signaling mediators was blocked by icatibant and dominant-negative Akt, indicating a kinin B2 receptor-Akt-mediated event [15].
  • The B2 receptor antagonist HOE140 and the B1 receptor agonist des-Arg9-bradykinin failed to induce significant phosphorylation of the B2 receptor [16].
  • The binding of the agonist bradykinin to the B(2) receptor endogenously expressed on PC-12 cells led to the formation of receptor dimers, whereas the B(2) antagonist HOE140 did not induce dimerization, suggesting that B(2) receptor dimerization was linked to receptor activation [17].

Anatomical context of Icatibant

  • Icatibant also reduced the antigen-induced increase in eosinophils, eosinophil cationic protein, kinin, and IL-8 in nasal lavage fluid [3].
  • Other variables indicating a systemic inflammatory response (C-reactive protein, leukocyte neutral proteinase inhibitor) remained unaffected by Icatibant [18].
  • The respective K(i) values of 0.32, 1.37 and 156 nM were obtained for bradykinin, HOE140 and D-Arg[Hyp3,D-Phe7,Leu8]bradykinin competing for radioligand binding to lamina II of sheep spinal cord sections [19].
  • Intranasal (i.n.) administration of MEN16132 (0.01-0.3 nmol/nostril) reduced, in a dose-dependent and long-lasting manner, the nasal mucosa plasma protein extravasation induced by BK (100 nmol/nostril), and it exerted a complete inhibition at about 30-fold lower dose than icatibant [20].
  • BK homologous curves performed with lung membranes after treatment with the antagonist MEN16132 or Icatibant (10 nM) displayed only the low affinity site [21].

Associations of Icatibant with other chemical compounds


Gene context of Icatibant

  • After gene delivery, human kallikrein mRNA was identified at the injured vessel and a 3-fold increase occurred in kininogenase activity. cAMP and cGMP levels in balloon-injured aorta increased significantly at 4, 7, and 14 days after kallikrein gene delivery, but icatibant abolished the increase [27].
  • Treatment of SaM-1 cells with BK increased the synthesis of both IL-6 and PGE(2) and the increase in both was blocked by HOE140 (B2R antagonist), but not by Des-Arg(9)-[Leu(8)]-BK (B1R antagonist) [28].
  • The expression of COX-2 induced by BK in DRG cells was inhibited by a BK B2 receptor antagonist, HOE140, but not a B1 receptor antagonist, Lys-des-Arg9, (Leu8)-BK [29].
  • Preincubation of hepatoma cells for 1 h with interleukin-1 alpha (IL-1 alpha) alone reduced T-kininogen concentrations by 37%, and this effect was blocked by co-addition of HOE140 [30].
  • The effect was blocked by a B2 receptor antagonist (HOE140) and specific inhibitors of VEGF receptor tyrosine kinases (Tki) and NOS [31].

Analytical, diagnostic and therapeutic context of Icatibant

  • Prevention with icatibant of anaphylactoid reactions to ACE inhibitor during LDL apheresis [32].
  • Covalent coupling of the receptor to bradykinin or HOE140, followed by Western blotting and immunoprinting with specific anti-ligand antibodies confirmed that the major ligand-binding form of the receptor is of 69 kDa [33].
  • Anaphylactoid reactions during hemodialysis were completely prevented by icatibant even after pre-treatment with ENA and in the presence of high BK concentrations [34].
  • These protective effects of Z13752A during ischaemia and reperfusion were abolished by the administration of icatibant (0.3 mg kg(-1), i.v.) a selective antagonist of bradykinin at B(2) receptors; the ischaemic changes in dogs given both icatibant and Z13752A were similar to those in the controls [35].
  • A KAL antibody or HOE140 (kinin B(2)-receptor antagonist) completely abolished this beneficial effect of IPC (36.6 and 53.0 U l(-1)) when added to the perfusion medium during the reperfusion cycles of IPC prior to the 30 min ischaemia [36].


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  2. Angiotensin-(1-7) induces bradykinin-mediated hypotensive responses in anesthetized rats. Abbas, A., Gorelik, G., Carbini, L.A., Scicli, A.G. Hypertension (1997) [Pubmed]
  3. Role of kinins in seasonal allergic rhinitis: icatibant, a bradykinin B2 receptor antagonist, abolishes the hyperresponsiveness and nasal eosinophilia induced by antigen. Turner, P., Dear, J., Scadding, G., Foreman, J.C. J. Allergy Clin. Immunol. (2001) [Pubmed]
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  13. Cloning and functional characterization of the ornithokinin receptor. Recognition of the major kinin receptor antagonist, HOE140, as a full agonist. Schroeder, C., Beug, H., Müller-Esterl, W. J. Biol. Chem. (1997) [Pubmed]
  14. The agonist binding site on the bovine bradykinin B2 receptor is adjacent to a sulfhydryl and is differentiated from the antagonist binding site by chemical cross-linking. Herzig, M.C., Leeb-Lundberg, L.M. J. Biol. Chem. (1995) [Pubmed]
  15. Kallikrein/kinin protects against myocardial apoptosis after ischemia/reperfusion via Akt-glycogen synthase kinase-3 and Akt-Bad.14-3-3 signaling pathways. Yin, H., Chao, L., Chao, J. J. Biol. Chem. (2005) [Pubmed]
  16. Ligand-induced phosphorylation/dephosphorylation of the endogenous bradykinin B2 receptor from human fibroblasts. Blaukat, A., Alla, S.A., Lohse, M.J., Müller-Esterl, W. J. Biol. Chem. (1996) [Pubmed]
  17. Involvement of the amino terminus of the B(2) receptor in agonist-induced receptor dimerization. AbdAlla, S., Zaki, E., Lother, H., Quitterer, U. J. Biol. Chem. (1999) [Pubmed]
  18. Bradykinin B2-receptor antagonism attenuates fatal cardiocirculatory breakdown induced by severe experimental pancreatitis. Yekebas, E., Treede, H., Jochum, M., Gippner-Steppert, C., Bloechle, C., Knoefel, W.T., Scholz, J., Fink, E., Izbicki, J.R. Crit. Care Med. (2000) [Pubmed]
  19. Distribution of bradykinin B2 receptors in sheep brain and spinal cord visualized by in vitro autoradiography. Murone, C., Paxinos, G., McKinley, M.J., Oldfield, B.J., Muller-Esterl, W., Mendelsohn, F.A., Chai, S.Y. J. Comp. Neurol. (1997) [Pubmed]
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  21. Comparative antagonist pharmacology at the native mouse bradykinin B(2) receptor: radioligand binding and smooth muscle contractility studies. Meini, S., Cucchi, P., Bellucci, F., Catalani, C., Giuliani, S., Santicioli, P., Maggi, C.A. Br. J. Pharmacol. (2007) [Pubmed]
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  24. Blood pressure responses to acute or chronic captopril in mice with disruption of bradykinin B2-receptor gene. Emanueli, C., Angioni, G.R., Anania, V., Spissu, A., Madeddu, P. J. Hypertens. (1997) [Pubmed]
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  29. The long-term exposure of rat cultured dorsal root ganglion cells to bradykinin induced the release of prostaglandin E2 by the activation of cyclooxygenase-2. Inoue, A., Iwasa, M., Nishikura, Y., Ogawa, S., Nakasuka, A., Nakata, Y. Neurosci. Lett. (2006) [Pubmed]
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  34. Anaphylactoid reactions during hemodialysis in sheep are ACE inhibitor dose-dependent and mediated by bradykinin. Krieter, D.H., Grude, M., Lemke, H.D., Fink, E., Bönner, G., Schölkens, B.A., Schulz, E., Müller, G.A. Kidney Int. (1998) [Pubmed]
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