(1R)-1-[(2R)-6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl]-2-{[(2R)-2-[(2S)-6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl]-2-hydroxyethyl]amino}ethan-1-ol hydrochloride

• ChemBase ID: 72738
• Molecular Formular: C22H26ClF2NO4
• Molecular Mass: 441.8959464
• Monoisotopic Mass: 441.15184244
• SMILES: c1c(cc2c(c1)O[C@H](CC2)[C@@H](CNC[C@H]([C@@H]1CCc2c(O1)ccc(c2)F)O)O)F.Cl
• Canonical SMILES: O[C@@H]([C@@H]1CCc2c(O1)ccc(c2)F)CNC[C@H]([C@H]1CCc2c(O1)ccc(c2)F)O.Cl
• InChI: InChI=1S/C22H25F2NO4.ClH/c23-15-3-7-19-13(9-15)1-5-21(28-19)17(26)11-25-12-18(27)22-6-2-14-10-16(24)4-8-20(14)29-22;/h3-4,7-10,17-18,21-22,25-27H,1-2,5-6,11-12H2;1H/t17-,18-,21-,22+;/m1./s1
• InChIKey: JWEXHQAEWHKGCW-VCVZPGOSSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: (1R)-1-[(2R)-6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl]-2-{[(2R)-2-[(2S)-6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl]-2-hydroxyethyl]amino}ethan-1-ol hydrochloride; (1R)-1-[(2S)-6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl]-2-{[(2R)-2-[(2R)-6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl]-2-hydroxyethyl]amino}ethan-1-ol hydrochloride
• IUPAC Traditional name: dexnebivolol hydrochloride; (1R)-1-[(2S)-6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl]-2-{[(2R)-2-[(2R)-6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl]-2-hydroxyethyl]amino}ethan-1-ol hydrochloride
• Synonyms: Bystolic; R-67145; Nebivolol HCl; Nebivololum; Lobivon; Nebicard-5; Nebilet; Nebilong; Nebipill; Nodon; Nubeta; Nebivolol Hydrochloride

Database IDs

• CAS Number: 152520-56-4; 99200-09-6
• PubChem SID: 162037659
• PubChem CID: 24866733

CALCULATED PROPERTIES

• Acid pKa: 13.520145
• H Acceptors: 5
• H Donor: 3
• LogD (pH = 5.5): 0.19658114
• LogD (pH = 7.4): 1.7054241
• Log P: 3.208403
• Molar Refractivity: 103.3172 cm^3
• Polarizability: 40.23752 Å^3
• Polar Surface Area: 70.95 Å^2
• Rotatable Bonds: 6
• Lipinski's Rule of Five: true

PROPERTIES

Safety Information

• Storage Condition: -20°C

Pharmacology Properties

• Target: adrenergic receptor
• Mechanism of Action: Beta 1 -Adrenoceptor antagonist; Vasodilator

Product Information

• Salt Data: HCL; HCl
• Description: Isomers (1:1)
• Application(s): Antihypertensive agent; Exhibits antianginal and antiischaemic effects

DETAILS

Selleck Chemicals - S1549

Research Area

• Description: Cardiovascular Disease

Biological Activity

• Description: Nebivolol selectively inhibits β1-adrenoceptor with IC50 of 0.8 nM.
• Targets: β1-adrenoceptor
• IC50: 0.8 nM ^[1]
• In Vitro: Nebivolol shows high affinity and selectivity for beta 1-adrenergic receptor sites in a rabbit lung membrane preparation (K_i value = 0.9 nM and beta 2/beta 1 ratio = 50). ^[1] Nebivolol displays β1-adrenoceptor selectivity with the K_i(β2)/K_i(β1) value of 40.7 judged by competition experiments to ^3H-CGP 12.1777 in the presence of CGP 207.12 A (300 nM, K_iβ2) or ICI 118.551 (50 nM, K_iβ1). ^[2] Nebivolol reduces cell proliferation of human coronary smooth muscle cells (haCSMCs) and endothelial cells (haECs) in a concentration- and time-dependent maner. Nebivolol treatment for 7 days causes significant reduction in cell growth of haCSMCs with IC50 of 6.1 μM, and inhibits accelerated haCSMC proliferation stimulated by growth factors PDGF-BB, bFGF, and TGFβ with IC50 values of 6.8 μM, 6.4 μM and 7.7 μM, repectively. Nebivolol treatment (10^-5 M) of haCSMCs for 48 hours induces a moderate apoptosis of 23% and a decrease from 16% to 5% in the number of cells in S-phase. During Nebivolol incubation, NO formation of HaCEs increases, while endothelin-1 transcription and secretion are suppressed. ^[3]
• In Vivo: Administratiion of Nebivolol (initially by iv within 10 minutes of reperfusion and then orally) to rats with myocardial infarction (MI) reduces myocardial apoptosis, which is mediated by regulation of NO . Nebivolol, significantly, prevents left ventricular (LV) pressure changes, reduces total and regional apoptotic cardiomyocytes. Nebivolol treatment lowers mean blood pressure (MBP) in rats with MI slightly, but not significantly. ^[4]
• Clinical Trials: A Phase IV study of comparative effects of Nebivolol versus Metoprololon on fatigue and quality of life has been completed.
• Features: Nebivolol is highly cardioselective under certain circumstances.

Protocol

• Protocol: Cell Assay ^[3]
• Cell Lines: Human coronary smooth muscle cells (haCSMCs) and endothelial cells (haECs)
• Concentrations: Dissolved in 100% methanol and diluted with three volumes of growth medium to obtain a stock solution of 10^-3 M, final concentration 10^-7~10^-5 M
• Incubation Time: 1, 2, 4, 7 and 14 days
• Methods: Cells are exposed to different concentrations of Nebivolol (10^-7~10^-5 M) for 1, 2, 4, 7 and 14 days. Cell proliferation is analyzed by bromodeoxyuridine (BrdU) incorporation, and cell apoptosis is detected by PI or annexin V staining.
• Protocol: Animal Study ^[4]
• Animal Models: Male Sprague Dawley rat myocardial infarction (MI) model
• Formulation: Dissolved in DMSO and diluted in saline
• Doses: 2.0 mg/kg
• Administration: Gastric gavage once daily

References

• References: [1] Pauwels PJ, et al. Mol Pharmacol, 1988, 34(6), 843-851.
• References: [2] Brixius K, et al. Br J Pharmacol, 2001, 133(8), 1330-1338.
• References: [3] Brehm BR, et al. Cardiovasc Res, 2001, 49(2), 430-439.
• References: [4] Mercanoglu G, et al. Circ J, 2008, 72(4), 660-670.

REFERENCES

• Pauwels PJ, et al. Mol Pharmacol, 1988, 34(6), 843-851.
• Brixius K, et al. Br J Pharmacol, 2001, 133(8), 1330-1338.
• Brehm BR, et al. Cardiovasc Res, 2001, 49(2), 430-439.
• Mercanoglu G, et al. Circ J, 2008, 72(4), 660-670.
• Eur. Pat., 1985, Janssen, 145 067; CA, 104, 5773, (synth, pharmacol)
• Van de Water, A. et al., J. Cardiovasc. Pharmacol., 1988, 11, 552
• Van Lommen, G. et al., J. Pharm. Belg., 1990, 45, 355, (synth, sar)
• Fitzgerald, J.D. et al., Drug Invest., Suppl. 1, 1991, 3, 1, (rev, pharmacokinet, pharmacol)
• Midol-Monnet, M. et al., J. Pharm. Pharmacol., 1991, 43, 504
• Janssens, W.J., J. Pharm. Belg., 1992, 47, 323, (pharmacol, rev)
• Peeters, O.M. et al., Acta Cryst. C, 1993, 49, 2154, (cryst struct)
• McNeely, W. et al., Drugs, 1999, 57, 633-651, (rev)
• Martindale, The Extra Pharmacopoeia, 32nd edn., Pharmaceutical Press, 1999, 914