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Chemical Compound Review

Ivabradine     4-[3-[[(8R)-3,4-dimethoxy-8...

Synonyms: Procoralan, SureCN23472, CHEMBL471737, CHEBI:548872, LS-28023, ...
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Disease relevance of S 16257


High impact information on S 16257

  • Agents selectively reducing heart rate have been developed which act by specific inhibition of I(f), such as ivabradine; these drugs have a high potential for treatment of diseases where heart rate reduction is beneficial, such as angina and heart failure [5].
  • HCN3 currents revealed slow activation and deactivation kinetics and were effectively blocked by extracellular Cs+ and the bradycardic agent ivabradine [6].
  • There was no subtype-specificity for the steady-state block, with mean IC50 values of 0.99, 2.25, and 1.96 microM for cilobradine, ivabradine, and zatebradine, respectively [7].
  • AIMS: Ivabradine, a new I(f) inhibitor which acts specifically on the pacemaker activity of the sinoatrial node, is a pure heart rate lowering agent [8].
  • When administered before exercise, atenolol and ivabradine similarly reduced heart rate versus saline at rest and during exercise (154+/-2 and 155+/-9 vs 217+/-13 beats/min, respectively) [1].

Chemical compound and disease context of S 16257


Biological context of S 16257


Anatomical context of S 16257

  • We have investigated the block of f-channels of rabbit cardiac sino-atrial node cells by ivabradine, a novel heart rate-reducing agent [15].
  • In addition, S 16257 did not affect resting epicardial coronary artery diameter and only attenuated its increase during exercise, whereas propranolol reduced it at rest and maintained a significant constriction of these large vessels throughout the exercise period [4].
  • In guinea-pig papillary muscles, paced at a frequency of 1 Hz, increasing concentrations of S 16257 or UL-FS 49 (0.1 to 10 microM, 30 min exposure for each concentration) slightly prolonged AP repolarization [16].
  • 1. The effects of S-16257-2 (S57) and S-16260-2 (R60), the two enantiomers of a new bradycardic agent, were studied on human cloned K+ channels (hKv1.5) stably expressed in a mouse L cell line using the whole-cell configuration of the patch-clamp technique [17].
  • At the site of the large arteries, ivabradine produced a decrease in the MCSA of the thoracic but not of the abdominal aorta, as well as an increase in pulsatile change of the carotid diameter without change in the isobaric distensibility and MCSA [18].

Associations of S 16257 with other chemical compounds

  • The effects of selective heart rate reduction by ivabradine (If inhibitor) were compared to those of atenolol on exercise-induced ischaemia and stunning [1].
  • Pharmacokinetic parameters for ivabradine did not vary significantly after omeprazole (C(max): 45.0 +/- 36.6 vs 42.7 +/- 27.6 ng/mL, P = .98; AUC: 128 +/- 87 vs 126 +/- 63 ng/mL, P = .82) or lansoprazole administration (C(max): 45.0 +/- 36.6 vs 41.3 +/- 29.4 ng/mL, P = .70; AUC: 128 +/- 87 vs 123 +/- 50, P = .73) [14].
  • The effects of either metoprolol or ivabradine were assessed 15 min after experimental occlusion of a coronary artery (CAO), 28 days after CAO (drug gavage), and in vitro hearts (Langendorff apparatus) [10].
  • Clinical Effect of 'Pure' Heart Rate Slowing with a Prototype I (f) Current Inhibitor: Placebo-Controlled Experience with Ivabradine [19].
  • Unlike many rate-lowering agents, ivabradine reduces heart rate in a dose-dependent manner both at rest and during exercise without producing any negative inotropic or vasoconstrictor effect [20].

Gene context of S 16257


Analytical, diagnostic and therapeutic context of S 16257

  • The effects of ivabradine on heart rate were studied at rest and during bicycle exercise tests (at 85% of maximum workload) during 24-hour postdosing, and ivabradine and S-18982 plasma levels were determined simultaneously [26].
  • The activity of ivabradine under conditions of enhanced sympathoadrenergic activity has been addressed by investigating the effects of repeated oral administration in mice with sympathoadrenergic activation due to either stress, cardiac-restricted overexpression of beta(2)-adrenergic receptors (beta(2)AR), or beta-agonist administration [23].
  • 1. The effect of the bradycardic agent S 16257 on the main ionic mechanisms of diastolic depolarization in sinoatrial node cells isolated from rabbit heart, was investigated by the patch-clamp technique in whole-cell and macro-patch recordings [27].
  • By reducing HR during exercise, ivabradine simultaneously improved LVWth compared with saline (14 +/- 1% versus 7 +/- 1%, respectively) and subendocardial perfusion (microspheres) [3].
  • Ivabradine has been associated with a good safety profile during its clinical development and its safety will be further assessed by postmarketing surveillance and during on-going clinical trials [20].


  1. Heart rate reduction during exercise-induced myocardial ischaemia and stunning. Monnet, X., Colin, P., Ghaleh, B., Hittinger, L., Giudicelli, J.F., Berdeaux, A. Eur. Heart J. (2004) [Pubmed]
  2. Heart rate lowering by specific and selective I(f) current inhibition with ivabradine: a new therapeutic perspective in cardiovascular disease. DiFrancesco, D., Camm, J.A. Drugs (2004) [Pubmed]
  3. Effects of heart rate reduction with ivabradine on exercise-induced myocardial ischemia and stunning. Monnet, X., Ghaleh, B., Colin, P., de Curzon, O.P., Giudicelli, J.F., Berdeaux, A. J. Pharmacol. Exp. Ther. (2001) [Pubmed]
  4. Coronary and hemodynamic effects of S 16257, a new bradycardic agent, in resting and exercising conscious dogs. Simon, L., Ghaleh, B., Puybasset, L., Giudicelli, J.F., Berdeaux, A. J. Pharmacol. Exp. Ther. (1995) [Pubmed]
  5. Serious workings of the funny current. DiFrancesco, D. Prog. Biophys. Mol. Biol. (2006) [Pubmed]
  6. The murine HCN3 gene encodes a hyperpolarization-activated cation channel with slow kinetics and unique response to cyclic nucleotides. Mistrík, P., Mader, R., Michalakis, S., Weidinger, M., Pfeifer, A., Biel, M. J. Biol. Chem. (2005) [Pubmed]
  7. Bradycardic and proarrhythmic properties of sinus node inhibitors. Stieber, J., Wieland, K., Stöckl, G., Ludwig, A., Hofmann, F. Mol. Pharmacol. (2006) [Pubmed]
  8. Efficacy of ivabradine, a new selective I(f) inhibitor, compared with atenolol in patients with chronic stable angina. Tardif, J.C., Ford, I., Tendera, M., Bourassa, M.G., Fox, K. Eur. Heart J. (2005) [Pubmed]
  9. Anti-ischemic effects of ivabradine, a selective heart rate-reducing agent, in exercise-induced myocardial ischemia in pigs. Vilaine, J.P., Bidouard, J.P., Lesage, L., Reure, H., Péglion, J.L. J. Cardiovasc. Pharmacol. (2003) [Pubmed]
  10. Comparison of a b-blocker and an if current inhibitor in rabbits with myocardial infarction. Langenbach, M.R., Schmitz-Spanke, S., Brockert, M., Schepan, M., Pomblum, V.J., Gams, E., Zirngibl, H., Schipke, J.D. The Journal of cardiovascular surgery. (2006) [Pubmed]
  11. Impact of increased heart rate on clinical outcomes in hypertension: implications for antihypertensive drug therapy. Palatini, P., Benetos, A., Julius, S. Drugs (2006) [Pubmed]
  12. Effect of graded heart rate reduction with ivabradine on myocardial oxygen consumption and diastolic time in exercising dogs. Colin, P., Ghaleh, B., Monnet, X., Hittinger, L., Berdeaux, A. J. Pharmacol. Exp. Ther. (2004) [Pubmed]
  13. Use-dependent inhibition of hHCN4 by ivabradine and relationship with reduction in pacemaker activity. Thollon, C., Bedut, S., Villeneuve, N., Cog??, F., Piffard, L., Guillaumin, J.P., Brunel-Jacquemin, C., Chomarat, P., Boutin, J.A., Peglion, J.L., Vilaine, J.P. Br. J. Pharmacol. (2007) [Pubmed]
  14. Lack of pharmacokinetic interaction between omeprazole or lansoprazole and ivabradine in healthy volunteers: an open-label, randomized, crossover, pharmacokinetic interaction clinical trial. Portolés, A., Calvo, A., Terleira, A., Laredo, L., Resplandy, G., Gorostiaga, C., Moreno, A. Journal of clinical pharmacology. (2006) [Pubmed]
  15. Current-dependent block of rabbit sino-atrial node I(f) channels by ivabradine. Bucchi, A., Baruscotti, M., DiFrancesco, D. J. Gen. Physiol. (2002) [Pubmed]
  16. Electrophysiological effects of S 16257, a novel sino-atrial node modulator, on rabbit and guinea-pig cardiac preparations: comparison with UL-FS 49. Thollon, C., Cambarrat, C., Vian, J., Prost, J.F., Peglion, J.L., Vilaine, J.P. Br. J. Pharmacol. (1994) [Pubmed]
  17. Mechanisms of block of a human cloned potassium channel by the enantiomers of a new bradycardic agent: S-16257-2 and S-16260-2. Delpón, E., Valenzuela, C., Pérez, O., Franqueza, L., Gay, P., Snyders, D.J., Tamargo, J. Br. J. Pharmacol. (1996) [Pubmed]
  18. Effect of chronic heart rate reduction with ivabradine on carotid and aortic structure and function in normotensive and hypertensive rats. Albaladejo, P., Carusi, A., Apartian, A., Lacolley, P., Safar, M.E., Bénétos, A. J. Vasc. Res. (2003) [Pubmed]
  19. Clinical Effect of 'Pure' Heart Rate Slowing with a Prototype I (f) Current Inhibitor: Placebo-Controlled Experience with Ivabradine. Borer, J.S. Advances in cardiology. (2006) [Pubmed]
  20. Novel I(f) Current Inhibitor Ivabradine: Safety Considerations. Savelieva, I., Camm, A.J. Advances in cardiology. (2006) [Pubmed]
  21. Properties of ivabradine-induced block of HCN1 and HCN4 pacemaker channels. Bucchi, A., Tognati, A., Milanesi, R., Baruscotti, M., Difrancesco, D. J. Physiol. (Lond.) (2006) [Pubmed]
  22. Effects of Hypericum perforatum on Ivabradine Pharmacokinetics in Healthy Volunteers: An Open-Label, Pharmacokinetic Interaction Clinical Trial. Portolés, A., Terleira, A., Calvo, A., Martínez, I., Resplandy, G. Journal of clinical pharmacology. (2006) [Pubmed]
  23. I(f) channel inhibitor ivabradine lowers heart rate in mice with enhanced sympathoadrenergic activities. Du, X.J., Feng, X., Gao, X.M., Tan, T.P., Kiriazis, H., Dart, A.M. Br. J. Pharmacol. (2004) [Pubmed]
  24. Simultaneous determination of ivabradine and its metabolites in human plasma by liquid chromatography--tandem mass spectrometry. François-Bouchard, M., Simonin, G., Bossant, n.u.l.l., Boursier-Neyret, C. J. Chromatogr. B Biomed. Sci. Appl. (2000) [Pubmed]
  25. Electrophysiological effects of a single intravenous administration of ivabradine (S 16257) in adult patients with normal baseline electrophysiology. Camm, A.J., Lau, C.P. Drugs in R&D. (2003) [Pubmed]
  26. Pharmacokinetic-pharmacodynamic modeling of the effects of ivabradine, a direct sinus node inhibitor, on heart rate in healthy volunteers. Ragueneau, I., Laveille, C., Jochemsen, R., Resplandy, G., Funck-Brentano, C., Jaillon, P. Clin. Pharmacol. Ther. (1998) [Pubmed]
  27. Mode of action of bradycardic agent, S 16257, on ionic currents of rabbit sinoatrial node cells. Bois, P., Bescond, J., Renaudon, B., Lenfant, J. Br. J. Pharmacol. (1996) [Pubmed]
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