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Chemical Compound Review

LS-21585     (2S)-2-[[(3aS,7aS)-1-[[2- [(2S)-2-[[(2S)-2...

Synonyms: AC1L2G0N, 138614-30-9, C59H89N19O13S.C2H4O2, 130308-48-4 (Parent), Icatibant acetate [USAN]
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Disease relevance of Icatibant

  • Bradykinin was released, and the bradykinin receptor antagonist HOE-140 blocked the effects of iberiotoxin on coronary hemodynamic and metabolic parameters during myocardial ischemia [1].
  • However, when HOE 140 was administered during the initial reflow period following 5 minutes of ischemia, protection was no longer abolished (15.6 +/- 3.9% infarction versus 13.3 +/- 3.8% without HOE 140, P = NS) [2].
  • Because neither enalaprilat nor HOE 140 affected these changes, the enhanced overflow of cGMP and 6-ketoprostaglandin F1 alpha is likely to reflect the actions of other hypersensitivity mediators (eg, histamine and leukotrienes) [3].
  • In the ascitic form of S-180, i.p. administration of HOE 140 at 13 microg/kg/12 h initiated immediately after tumor inoculation significantly suppressed formation of S-180 tumor ascites; the life span of ascitic S-180 tumor-bearing mice was prolonged at the same dose of HOE 140 [4].
  • In HOE/ENAL, pretreatment with HOE 140 prevented the decrease in albuminuria observed in ENAL [5].

High impact information on Icatibant

  • DABK-induced leukocyte trafficking was antagonized by the B(1) receptor antagonist des-arg(10)HOE 140 but not by the B(2) receptor antagonist HOE 140 [6].
  • The presence of captopril, an inhibitor of bradykinin degradation by kininase II, drastically potentiated parasitic invasion of HUVECs and CHO-B(2)R, but not of mock-transfected CHO cells, whereas the B(2)R antagonist HOE 140 or monoclonal antibody MBK3 to bradykinin blocked these effects [7].
  • HOE 140 led to an increase in coronary vascular resistance (P < .001) and a decrease in coronary blood flow (P < .001) [8].
  • Mean arterial pressure was reduced by ramipril compared with the control group (-8 +/- 2 versus +7 +/- 2 mm Hg, P = .03), and this effect was not blunted by the addition of HOE 140 (-7 +/- 3 mm Hg) [9].
  • After bradykinin B2 receptor blockade, there was a reduction in flow-dependent dilation (23.4 +/- 6.9% to 3.9 +/- 6.0%, P < .001), the extent of which correlated with the degree of basal vasoconstriction after HOE 140 in the same vessel segment (P < .05) [8].

Chemical compound and disease context of Icatibant


Biological context of Icatibant


Anatomical context of Icatibant

  • Interestingly, the peptidic HOE 140 compound and an original nonpeptidic compound LF 16 0335, which both behaved as inverse agonists of the wild-type receptor expressed in COS-7 cells, became potent and efficient agonists of the two constitutively activated mutant N113A and W256F receptors [20].
  • Following administration of HOE 140, functional hyperaemia in the soleus muscle was unaffected (blood flow, 17.8 +/- 2.2 ml min-1 (100 g tissue)-1, n = 6; n.s.) white blood flow in the gastrocnemius muscle was reduced to 21.8 +/- 6.0 ml min-1 (100 g tissue)-1 (n = 6; P < 0.05) [21].
  • D-Arg0[Hyp3,Thi5,D-Tic7,Oic8]bradykinin (HOE-140) is a potent (Ki = 0.11 nM) inhibitor of [3H]bradykinin binding to bradykinin B2 receptors found on human IMR-90 fetal lung fibroblasts [22].
  • The B2 antagonist, HOE-140, was a very weak inhibitor of the B1 response in human ileum and inactive in rabbit aorta [23].
  • 3. HOE-140 (1 microg kg(-1)) administered in the same manner, decreased mononuclear cell and eosinophil infiltration in the bronchoalveolar lavage fluid (BALF) of OA-sensitized mice [24].

Associations of Icatibant with other chemical compounds

  • Moreover, enalaprilat (1 mumol/L) completely and immediately restored the response of the B2 receptor, desensitized by the agonist (1 mumol/L [Hyp3-Tyr(Me)8]BK); this effect was blocked by the antagonist, HOE 140 [25].
  • The extravasation of the Evans blue dye evoked by OVA (5%, 2 min) in sensitized guinea pigs was reduced by HOE 140 (45%) when the animals were perfused after 5 min and by 39% when perfusion was performed at 10 min [26].
  • The increase in RL induced by cold air after L-NAME was abolished by the tachykinin NK2-receptor antagonist SR 48968 or the kinin B2-receptor antagonist, HOE 140 [18].
  • In contrast, N(G)-nitro-l-arginine methyl ester (10 mg/kg and 0.1 mg. kg(-1). min(-1) iv) and the bradykinin B(2)-receptor antagonist HOE-140 (20 microg/kg and 10 microg x kg(-1) x min(-1) iv) markedly lowered the medullary vasodilation at the highest doses of ANG II only [27].
  • Topically applied BK (3 micromol/l) induced vasodilation (62 +/- 12%) after the administration of N(omega)-nitro-L-arginine methyl ester (L-NAME) and indomethacin, which was inhibited by endothelial impairment or by the BK(2) receptor antagonist HOE-140 (0.3 micromol/l) [28].

Gene context of Icatibant

  • The increases in IL-6 protein and total mRNA were inhibited by the selective B(2) receptor antagonist HOE-140 but not by the selective B(1) receptor antagonist desArg(9)(Leu(8))-BK [29].
  • HOE-140 markedly inhibited the rise in IL-1beta and TNF-alpha levels in pouch fluid triggered by both stimuli [30].
  • Ligand efficacy of synthetic ligand HOE 140 decreased in the order B(o)R > CKR-2 > CKR-1 > B(2)R, whereas the efficacy of the endogenous kinin ligand was unchanged [31].
  • The stimulatory effect of BK on the IL-1beta- or TNFalpha-stimulated IL-8 production was reduced in the presence of BK B2 receptor antagonist HOE 140, whereas the B1 receptor antagonist Lys-(des-arg9, Leu8)-BK had no effect [32].
  • The BK response was decreased (5.09 +/- 0.30, N = 6 to 1.57 +/- 0.12, N = 7, P < 0.001) by the B2 receptor antagonist HOE 140 (0.1 microM, 15 min), while the B1 receptor antagonist des-Arg9-[Leu8]-BK (1 microM, 15 min) had no effect on BK or des-Arg10-Kal actions [33].

Analytical, diagnostic and therapeutic context of Icatibant


  1. Bradykinin mediation of Ca(2+)-activated K+ channels regulates coronary blood flow in ischemic myocardium. Node, K., Kitakaze, M., Kosaka, H., Minamino, T., Hori, M. Circulation (1997) [Pubmed]
  2. Role of bradykinin in protection of ischemic preconditioning in rabbit hearts. Goto, M., Liu, Y., Yang, X.M., Ardell, J.L., Cohen, M.V., Downey, J.M. Circ. Res. (1995) [Pubmed]
  3. Protective role of bradykinin in cardiac anaphylaxis. Coronary-vasodilating and antiarrhythmic activities mediated by autocrine/paracrine mechanisms. Rubin, L.E., Levi, R. Circ. Res. (1995) [Pubmed]
  4. Modulation of enhanced vascular permeability in tumors by a bradykinin antagonist, a cyclooxygenase inhibitor, and a nitric oxide scavenger. Wu, J., Akaike, T., Maeda, H. Cancer Res. (1998) [Pubmed]
  5. The antiproteinuric action of angiotensin-converting enzyme is dependent on kinin. Hutchison, F.N., Cui, X., Webster, S.K. J. Am. Soc. Nephrol. (1995) [Pubmed]
  6. Association between kinin B(1) receptor expression and leukocyte trafficking across mouse mesenteric postcapillary venules. McLean, P.G., Ahluwalia, A., Perretti, M. J. Exp. Med. (2000) [Pubmed]
  7. Host cell invasion by Trypanosoma cruzi is potentiated by activation of bradykinin B(2) receptors. Scharfstein, J., Schmitz, V., Morandi, V., Capella, M.M., Lima, A.P., Morrot, A., Juliano, L., Müller-Esterl, W. J. Exp. Med. (2000) [Pubmed]
  8. Role of endogenous bradykinin in human coronary vasomotor control. Groves, P., Kurz, S., Just, H., Drexler, H. Circulation (1995) [Pubmed]
  9. Bradykinin antagonism inhibits the antigrowth effect of converting enzyme inhibition in the dog myocardium after discrete transmural myocardial necrosis. McDonald, K.M., Mock, J., D'Aloia, A., Parrish, T., Hauer, K., Francis, G., Stillman, A., Cohn, J.N. Circulation (1995) [Pubmed]
  10. A specific B2-bradykinin receptor antagonist HOE 140 abolishes the antihypertrophic effect of ramipril. Linz, W., Schölkens, B.A. Br. J. Pharmacol. (1992) [Pubmed]
  11. The involvement of kallikrein-kinin system in diabetes type I (insulitis). Zuccollo, A., Navarro, M., Frontera, M., Cueva, F., Carattino, M., Catanzaro, O.L. Immunopharmacology (1999) [Pubmed]
  12. Development of hyperthermia and hyperalgesia following intracerebroventricular administration of endotoxin in the rat: effect of kinin B1 and B2 receptor antagonists. Walker, K., Dray, A., Perkins, M. Immunopharmacology (1996) [Pubmed]
  13. Potentiation of nicotinic currents by bradykinin in the paratracheal ganglia neurons of rats. Rong Zhou, J., Shirasaki, T., Soeda, F., Takahama, K. Eur. J. Pharmacol. (2006) [Pubmed]
  14. Effect of icatibant, a bradykinin B2 receptor antagonist, on the development of experimental ulcerative colitis in mice. Arai, Y., Takanashi, H., Kitagawa, H., Wirth, K.J., Okayasu, I. Dig. Dis. Sci. (1999) [Pubmed]
  15. Bradykinin B2 receptors on skeletal muscle are coupled to inositol 1,4,5-trisphosphate formation. Rabito, S.F., Minshall, R.D., Nakamura, F., Wang, L.X. Diabetes (1996) [Pubmed]
  16. Role of bradykinin B2 and B1 receptors in the local, remote, and systemic inflammatory responses that follow intestinal ischemia and reperfusion injury. Souza, D.G., Lomez, E.S., Pinho, V., Pesquero, J.B., Bader, M., Pesquero, J.L., Teixeira, M.M. J. Immunol. (2004) [Pubmed]
  17. Angiotensin-(1-7) contributes to the antihypertensive effects of blockade of the renin-angiotensin system. Iyer, S.N., Ferrario, C.M., Chappell, M.C. Hypertension (1998) [Pubmed]
  18. Endogenous nitric oxide inhibits bronchoconstriction induced by cold-air inhalation in guinea pigs: role of kinins. Yoshihara, S., Nadel, J.A., Figini, M., Emanueli, C., Pradelles, P., Geppetti, P. Am. J. Respir. Crit. Care Med. (1998) [Pubmed]
  19. Kinin B2 receptors mediate blockade of atrial natriuretic peptide natriuresis induced by glucose or feeding in fasted rats. Croxatto, H.R., Figueroa, X.F., Roblero, J., Boric, M.P. Hypertension (1999) [Pubmed]
  20. Constitutive activation of the human bradykinin B2 receptor induced by mutations in transmembrane helices III and VI. Marie, J., Koch, C., Pruneau, D., Paquet, J.L., Groblewski, T., Larguier, R., Lombard, C., Deslauriers, B., Maigret, B., Bonnafous, J.C. Mol. Pharmacol. (1999) [Pubmed]
  21. The role of bradykinin in the regulation of blood flow to hindlimb muscle groups of the anaesthetized cat. Poucher, S.M., Garcia, S., Brooks, R. J. Physiol. (Lond.) (1998) [Pubmed]
  22. Synthesis, characterization, and conformational analysis of the D/L-Tic7 stereoisomers of the bradykinin receptor antagonist D-Arg0[Hyp3,Thi5,D-Tic7,Oic8]bradykinin. Sawutz, D.G., Salvino, J.M., Seoane, P.R., Douty, B.D., Houck, W.T., Bobko, M.A., Doleman, M.S., Dolle, R.E., Wolfe, H.R. Biochemistry (1994) [Pubmed]
  23. Evidence of a bradykinin B1 receptor in human ileum: pharmacological comparison to the rabbit aorta B1 receptor. Zuzack, J.S., Burkard, M.R., Cuadrado, D.K., Greer, R.A., Selig, W.M., Whalley, E.T. J. Pharmacol. Exp. Ther. (1996) [Pubmed]
  24. Implication of the bradykinin receptors in antigen-induced pulmonary inflammation in mice. Eric, J., Gabra, B.H., Sirois, P. Br. J. Pharmacol. (2003) [Pubmed]
  25. Potentiation of the actions of bradykinin by angiotensin I-converting enzyme inhibitors. The role of expressed human bradykinin B2 receptors and angiotensin I-converting enzyme in CHO cells. Minshall, R.D., Tan, F., Nakamura, F., Rabito, S.F., Becker, R.P., Marcic, B., Erdös, E.G. Circ. Res. (1997) [Pubmed]
  26. Role of kinins in the vascular extravasation evoked by antigen and mediated by tachykinins in guinea pig trachea. Bertrand, C., Nadel, J.A., Yamawaki, I., Geppetti, P. J. Immunol. (1993) [Pubmed]
  27. Angiotensin II and renal medullary blood flow in Lyon rats. Sarkis, A., Liu, K.L., Lo, M., Benzoni, D. Am. J. Physiol. Renal Physiol. (2003) [Pubmed]
  28. Hydrogen peroxide acts as an EDHF in the piglet pial vasculature in response to bradykinin. Lacza, Z., Puskar, M., Kis, B., Perciaccante, J.V., Miller, A.W., Busija, D.W. Am. J. Physiol. Heart Circ. Physiol. (2002) [Pubmed]
  29. Bradykinin induces interleukin-6 production in human airway smooth muscle cells: modulation by Th2 cytokines and dexamethasone. Huang, C.D., Tliba, O., Panettieri, R.A., Amrani, Y. Am. J. Respir. Cell Mol. Biol. (2003) [Pubmed]
  30. Effect of a kinin B2 receptor antagonist on LPS- and cytokine-induced neutrophil migration in rats. Santos, D.R., Calixto, J.B., Souza, G.E. Br. J. Pharmacol. (2003) [Pubmed]
  31. Changes in amino-terminal portion of human B2 receptor selectively increase efficacy of synthetic ligand HOE 140 but not of cognate ligand bradykinin. Schroeder, C., Breit, A., Böning, H., Dedio, J., Gera, L., Stewart, J., Müller-Esterl, W. Am. J. Physiol. Heart Circ. Physiol. (2003) [Pubmed]
  32. Bradykinin upregulates IL-8 production in human gingival fibroblasts stimulated by interleukin-1beta and tumor necrosis factor alpha. Brunius, G., Domeij, H., Gustavsson, A., Yucel-Lindberg, T. Regul. Pept. (2005) [Pubmed]
  33. Effects of kinins upon cytosolic calcium concentrations in mouse mesangial cells. Campos, A.H., Calixto, J.B., Schor, N. Immunopharmacology (1999) [Pubmed]
  34. Bradykinin signaling counteracts cAMP-elicited aquaporin 2 translocation in renal cells. Tamma, G., Carmosino, M., Svelto, M., Valenti, G. J. Am. Soc. Nephrol. (2005) [Pubmed]
  35. Chronic angiotensin II infusion but not bradykinin blockade abolishes the antiproteinuric response to angiotensin-converting enzyme inhibition in established adriamycin nephrosis. Wapstra, F.H., Navis, G., de Jong, P.E., de Zeeuw, D. J. Am. Soc. Nephrol. (2000) [Pubmed]
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