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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].

References

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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]
  4. The renal antifibrotic effects of angiotensin-converting enzyme inhibition involve bradykinin B2 receptor activation in angiotensin II-dependent hypertension. Seccia, T.M., Belloni, A.S., Guidolin, D., Sticchi, D., Nussdorfer, G.G., Pessina, A.C., Rossi, G.P. J. Hypertens. (2006) [Pubmed]
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  12. Effects of a bradykinin receptor antagonist (HOE140) on taurocholate-induced acute pancreatitis in rats. Kanbe, T., Naruse, S., Kitagawa, M., Nakae, Y., Hayakawa, T. Pancreas (1996) [Pubmed]
  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]
  20. MEN16132, a novel potent and selective nonpeptide kinin B2 receptor antagonist: in vivo activity on bradykinin-induced bronchoconstriction and nasal mucosa microvascular leakage in anesthetized guinea pigs. Valenti, C., Cialdai, C., Giuliani, S., Lecci, A., Tramontana, M., Meini, S., Quartara, L., Maggi, C.A. J. Pharmacol. Exp. Ther. (2005) [Pubmed]
  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]
  22. Role of kinins in the pathophysiology of myocardial ischemia. In vitro and in vivo studies. Linz, W., Wiemer, G., Schölkens, B.A. Diabetes (1996) [Pubmed]
  23. Bradykinin B(2) receptor antagonism attenuates blood pressure response to acute angiotensin-converting enzyme inhibition in normal men. Squire, I.B., O'Kane, K.P., Anderson, N., Reid, J.L. Hypertension (2000) [Pubmed]
  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]
  25. The nonpeptide B2 receptor antagonist FR173657: inhibition of effects of bradykinin related to its role in nociception. Griesbacher, T., Amann, R., Sametz, W., Diethart, S., Juan, H. Br. J. Pharmacol. (1998) [Pubmed]
  26. Bradykinin B2 and GPR100 receptors: a paradigm for receptor signal transduction pharmacology. Meini, S., Bellucci, F., Cucchi, P., Giuliani, S., Quartara, L., Giolitti, A., Zappitelli, S., Rotondaro, L., Boels, K., Maggi, C.A. Br. J. Pharmacol. (2004) [Pubmed]
  27. Kallikrein gene delivery inhibits vascular smooth muscle cell growth and neointima formation in the rat artery after balloon angioplasty. Murakami, H., Yayama, K., Miao, R.Q., Wang, C., Chao, L., Chao, J. Hypertension (1999) [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]
  30. Bradykinin decreases T-kininogen synthesis in a rat hepatoma cell line: evidence of bradykinin B2-type receptors. Raymond, P., Bouvier, M., Drapeau, G., Blais, C., Morais, R., Adam, A. Peptides (1996) [Pubmed]
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  33. Structural features of the human bradykinin B2 receptor probed by agonists, antagonists, and anti-idiotypic antibodies. Alla, S.A., Buschko, J., Quitterer, U., Maidhof, A., Haasemann, M., Breipohl, G., Knolle, J., Müller-Esterl, W. J. Biol. Chem. (1993) [Pubmed]
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