Nebivolol (also known as R-65824) potently and selectively inhibits β1-adrenoceptor with IC50 of 0.8 NM. Nebivolol demonstrates high selectivity and affinity for beta 1-adrenergic receptor sites in a lung membrane preparation from a rabbit (beta 2/beta 1 ratio = 50 and Ki value = 0.9 nM). With a Ki(β2)/Ki(β1) value of 40.7, which competition experiments judge to be 3H-CGP 12.1777 in the presence of CGP 207.12 A (300 nM, Kiβ2) or ICI 118.551 (50 nM, Kiβ1), Nebivolol exhibits β1-adrenoceptor selectivity.

Physicochemical Properties

Molecular Formula	C22H26CLF2NO4
Molecular Weight	441.8960
Exact Mass	441.151
Elemental Analysis	C, 59.80; H, 5.93; Cl, 8.02; F, 8.60; N, 3.17; O, 14.48
CAS #	152520-56-4
Related CAS #	Nebivolol; 118457-14-0
PubChem CID	24866733
Appearance	White to off-white solid powder
Boiling Point	600.5ºC at 760 mmHg
Melting Point	220-222ºC
Flash Point	316.9ºC
Vapour Pressure	2.88E-15mmHg at 25°C
LogP	3.556
Hydrogen Bond Donor Count	4
Hydrogen Bond Acceptor Count	7
Rotatable Bond Count	6
Heavy Atom Count	30
Complexity	483
Defined Atom Stereocenter Count	4
SMILES	Cl[H].FC1C([H])=C([H])C2=C(C=1[H])C([H])([H])C([H])([H])[C@]([H])(C([H])(C([H])([H])N([H])C([H])([H])[C@@]([H])([C@]1([H])C([H])([H])C([H])([H])C3C([H])=C(C([H])=C([H])C=3O1)F)O[H])O[H])O2
InChi Key	JWEXHQAEWHKGCW-BIISKSHESA-N
InChi Code	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+;/m0./s1
Chemical Name	(1S)-1-[(2S)-6-fluoro-3,4-dihydro-2H-chromen-2-yl]-2-[[(2S)-2-[(2R)-6-fluoro-3,4-dihydro-2H-chromen-2-yl]-2-hydroxyethyl]amino]ethanol;hydrochloride
Synonyms	Silostar; Bystolic; R 67145; R-67145; R67145; Nebivolol HCl; Nebivolol Hydrochloride
HS Tariff Code	2934.99.9001
Storage	Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

Targets	β1-adrenoceptor ( IC50 = 0.8 nM )
ln Vitro	Nebivolol demonstrates high affinity and selectivity for beta 1-adrenergic receptor sites in a rabbit lung membrane preparation (Ki value = 0.9 nM and beta 2/beta 1 ratio = 50).[1] Nebivolol demonstrates selectivity for β1-adrenoceptors with a Ki(β2)/Ki(β1) value of 40.7, as determined by competition experiments to 3H-CGP 12.1777 when CGP 207.12 A (300 nM, Kiβ2) or ICI 118.551 (50 nM, Kiβ1) are present.[2] Nebivolol inhibits human endothelial cells (haECs) and coronary smooth muscle cells (haCSMCs) in a manner that is concentration- and time-dependent. After 7 days of treatment, a significant reduction in the cell growth of haCSMCs is observed with an IC50 of 6.1 μM. Additionally, the accelerated proliferation of haCSMCs stimulated by growth factors TGFβ, bFGF, and PDGF-BB is inhibited with IC50 values of 6.8 μM, 6.4 μM, and 7.7 μM, respectively. After giving haCSMCs a 10-to 5-microgram dose of nibevolol for 48 hours, 23% of the cells undergo moderate apoptosis, and the proportion of S-phase cells falls from 16% to 5%. HaCEs produce more NO during Nebivolol incubation, but endothelin-1 transcription and secretion are inhibited.[3]
ln Vivo	Nebivolol administration reduces myocardial apoptosis in rats with myocardial infarction (MI). This effect is mediated by regulation of NO and occurs first by intravenous injection within 10 minutes of reperfusion and then orally. Nebivolol decreases both total and localized apoptotic cardiomyocytes and considerably prevents variations in left ventricular (LV) pressure. Treatment with nevivolol slightly but not significantly lowers the mean blood pressure (MBP) in rats suffering from MI.[4]
Cell Assay	Nebivolol (10-7~10-5 M) is added to cells at varying concentrations for 1, 2, 4, 7, and 14 days. Bromodeoxyuridine (BrdU) incorporation is used to analyze cell proliferation, while PI or annexin V staining is used to identify cell apoptosis.
Animal Protocol	Male Sprague Dawley rat myocardial infarction (MI) model 2.0 mg/kg Gastric gavage once daily
References	[1]. Mol Pharmacol . 1988 Dec;34(6):843-51. [2]. Br J Pharmacol . 2001 Aug;133(8):1330-8. [3]. Cardiovasc Res . 2001 Feb 1;49(2):430-9. [4]. Circ J . 2008 Apr;72(4):660-70.
Additional Infomation	(S,R,R,R)-nebivolol hydrochloride is a hydrochloride obtained by reaction of (S,R,R,R)-nebivolol with one equivalent of hydrochloric acid. It contains a (S,R,R,R)-nebivolol(1+). It is an enantiomer of a (R,S,S,S)-nebivolol hydrochloride. A cardioselective ADRENERGIC BETA-1 RECEPTOR ANTAGONIST (beta-blocker) that functions as a VASODILATOR through the endothelial L-arginine/ NITRIC OXIDE system. It is used to manage HYPERTENSION and chronic HEART FAILURE in elderly patients. See also: Nebivolol (has active moiety); Nebivolol hydrochloride; valsartan (component of).

Solubility Data

Solubility (In Vitro)

DMSO: 88~100 mg/mL (199.1~226.3 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.08 mg/mL (4.71 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (4.71 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: ≥ 2.08 mg/mL (4.71 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 4: 5% DMSO + 20% PEG300 + 5%Tween 80 + 70%ddH2O: 4.4mg/ml (9.96mM)  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.2630 mL	11.3148 mL	22.6296 mL
	5 mM	0.4526 mL	2.2630 mL	4.5259 mL
	10 mM	0.2263 mL	1.1315 mL	2.2630 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.