Betaxolol (Betoptima; Kerlone; Betoptic; Kerlon; SL-75212 HCl; ALO-140102) is a β1 adrenergic receptor antagonist/blocker with antihypertensive effects. It is applied to the management of glaucoma and hypertension. With an IC50 of 6 μM, betaxolol inhibits the β1 adrenergic receptor.

Physicochemical Properties

Molecular Formula	C18H29NO3
Molecular Weight	307.43
Exact Mass	307.21
Elemental Analysis	C, 70.32; H, 9.51; N, 4.56; O, 15.61
CAS #	63659-18-7
Related CAS #	Betaxolol hydrochloride; 63659-19-8; Levobetaxolol hydrochloride; 116209-55-3; Betaxolol-d5; 1189957-99-0; 63659-18-7; 93221-48-8 (S-isomer free base); 116209-55-3 (S-isomer HCl)
PubChem CID	2369
Appearance	White to off-white solid powder
Density	1.067 g/cm3
Boiling Point	448ºC at 760 mmHg
Melting Point	61-63°C
Flash Point	224.7ºC
LogP	2.784
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	4
Rotatable Bond Count	11
Heavy Atom Count	22
Complexity	286
Defined Atom Stereocenter Count	0
SMILES	O(C([H])([H])C([H])([H])C1C([H])=C([H])C(=C([H])C=1[H])OC([H])([H])C([H])(C([H])([H])N([H])C([H])(C([H])([H])[H])C([H])([H])[H])O[H])C([H])([H])C1([H])C([H])([H])C1([H])[H]
InChi Key	NWIUTZDMDHAVTP-UHFFFAOYSA-N
InChi Code	InChI=1S/C18H29NO3/c1-14(2)19-11-17(20)13-22-18-7-5-15(6-8-18)9-10-21-12-16-3-4-16/h5-8,14,16-17,19-20H,3-4,9-13H2,1-2H3
Chemical Name	1-[4-[2-(cyclopropylmethoxy)ethyl]phenoxy]-3-(propan-2-ylamino)propan-2-ol
Synonyms	SL-75212 HCl;ALO 140102; betaxolol; 63659-18-7; Betaxololum; Betoptic; Kerlone; Betaxololum [INN-Latin]; Betaxolol S; SL 75212; ALO-1401-02; SL 75212 HCl; Betaxolol Hydrochloride; Betaxolol HCL; Betoptima; Kerlone; Betoptic; Kerlon; SL75212 HCl; ALO140102
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
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	Beta1 Adrenergic Receptor
ln Vitro	In vitro activity: Betaxolol hydrochloride is a beta-adrenergic receptor blocker that is cardioselective.
ln Vivo	Animals treated with Betaxolol during cocaine withdrawal exhibited a significant attenuation of anxiety-like behavior characterized by increased time spent in the open arms and increased entries into the open arms compared to animals treated with only saline during cocaine withdrawal. In contrast, Betaxolol did not produce anxiolytic-like effects in control animals treated chronically with saline. Furthermore, treatment with Betaxolol during early cocaine withdrawal significantly decreased beta(1)-adrenergic receptor protein expression in the amygdala to levels comparable to those of control animals. Conclusions: The present findings suggest that the anxiolytic-like effect of Betaxolol on cocaine-induced anxiety may be related to its effect on amygdalar beta(1)-adrenergic receptors that are up-regulated during early phases of drug withdrawal. These data support the efficacy of Betaxolol as a potential effective pharmacotherapy in treating cocaine withdrawal-induced anxiety during early phases of abstinence.[1] Betaxolol hydrochloride (5 mg/kg via i.p. injection) was given 24 hours after the last chronic cocaine administration and again 44 hours later. When compared to animals treated with only saline during cocaine withdrawal, animals treated with betaxolol demonstrated a significant attenuation of anxiety-like behavior, as evidenced by increased time spent in the open arms and increased entries into the open arms. Chronic saline treatment of control animals did not result in anxiolytic-like effects from bexolol hydrochloride[1]. Compared to timolol or levobunolol, betaxolol hydrochloride results in less systemic beta 2- and possibly beta 1-adrenergic receptor blockade. When treating patients with reactive airway disease, betaxolol hydrochloride may be a safer option than levobunolol or timolol[2].
Cell Assay	Dissociated cortical cells from 16–18-day-old fetal rats are grown in 35 mm dishes in DMEM supplemented with L-glutamine (4 mM), glucose (6 g/L), penicillin (100 U/mL), streptomycin (100 μg/mL), and 10% hormonal supplemented medium that contains sodium selenite (0.3 μM), progesterone (0.2 μM), putrescine (600 μM), transferrin (1 mg/mL), insulin (250 μg/mL), putrescine (600 μM), progesterone (0.2 μM), and estradiol (0.1 pM). After that, the cultures are moved to a culture medium without hormone supplements. After adding L-glutamate, the mixture is incubated under normoxic conditions for an additional 4 hours. L-glutamate and betaxolol are added to the cultures simultaneously. In anoxic conditions, 95% N2/5% CO2 for 5 hours at 37 °C, are applied to the cultures in other experiments. Anoxia occurs first, and then bexolol. Next, the cells are swapped out for normoxic ones (95% O2/5% CO2) for three hours in order to achieve reoxygenation. Measuring the release of lactate dehydrogenase (LDH) into the supernatant of cell cultures following hypoxia/reoxygenation or glutamate exposure is a useful method for evaluating cellular injury. By monitoring NADH metabolism for two minutes at 340 nm, LDH activity is measured spectrophotometrically.
Animal Protocol	Male Sprague Dawley rats were administered intraperitoneal (i.p.) injections of cocaine (20 mg/kg) once daily for 14 days. Two days following the last cocaine injection, amygdala brain regions were micro-dissected and processed for Western blot analysis. Results showed that beta(1)-adrenergic receptor, but not beta(2)-adrenergic receptor expression was significantly increased in amygdala extracts of cocaine-withdrawn animals as compared to controls. This finding motivated further studies aimed at determining whether treatment with Betaxolol, a highly selective beta(1)-adrenergic receptor antagonist, could ameliorate cocaine withdrawal-induced anxiety. In these studies, Betaxolol (5 mg/kg via i.p. injection) was administered at 24 and then 44 h following the final chronic cocaine administration. Anxiety-like behavior was evaluated using the elevated plus maze test approximately 2 h following the last Betaxolol injection. Following behavioral testing, Betaxolol effects on beta(1)-adrenergic receptor protein expression were examined by Western blotting in amygdala extracts from rats undergoing cocaine withdrawal.[1] Dissolved in saline; 2.5 mg/kg; i.p. injection Rat with ischemia model
ADME/Pharmacokinetics	Absorption, Distribution and Excretion Absorption of an oral dose is complete. There is a small and consistent first-pass effect resulting in an absolute bioavailability of 89% ± 5% that is unaffected by the concomitant ingestion of food or alcohol. Metabolism / Metabolites Primarily hepatic. Approximately 15% of the dose administered is excreted as unchanged drug, the remainder being metabolites whose contribution to the clinical effect is negligible. Biological Half-Life 14-22 hours
Toxicity/Toxicokinetics	Hepatotoxicity Betaxolol therapy has been associated with a low rate of mild-to-moderate elevations of serum aminotransferase levels which are usually asymptomatic and transient and resolve even with continuation of therapy. There have been no well documented cases of clinically apparent, acute liver injury attributable to betaxolol. Thus, hepatotoxicity due to betaxolol must be very rare, if it occurs at all. Most commonly used beta-blockers have been linked to rare instances of clinically apparent liver injury, typically with onset within 2 to 12 weeks, a hepatocellular pattern of liver enzyme elevations, rapid recovery on withdrawal, and little evidence of hypersensitivity (rash, fever, eosinophilia) or autoantibody formation. Likelihood score: E (unlikely cause of clinically apparent liver injury). Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation Because of its relatively extensive excretion into breastmilk and minimal reported experience during breastfeeding, other beta-blocking agents may be preferred for systemic use, especially while nursing a newborn or preterm infant. Ophthalmic use of betaxolol by the mother should pose little risk to the breastfed infant, although some guidelines state that gel formulations are preferred over solutions. To substantially diminish the amount of drug that reaches the breastmilk after using eye drops, place pressure over the tear duct by the corner of the eye for 1 minute or more, then remove the excess solution with an absorbent tissue. ◉ Effects in Breastfed Infants A study of mothers taking beta-blockers during nursing found a numerically, but not statistically significant increased number of adverse reactions in those taking any beta-blocker. Although the ages of infants were matched to control infants, the ages of the affected infants were not stated. None of the mothers were taking betaxolol. Beta-adrenergic blocking drugs with breastmilk excretion characteristics similar to betaxolol have caused adverse effects in breastfed newborns. ◉ Effects on Lactation and Breastmilk Relevant published information on the effects of beta-blockade or betaxolol during normal lactation was not found as of the revision date. A study in 6 patients with hyperprolactinemia and galactorrhea found no changes in serum prolactin levels following beta-adrenergic blockade with propranolol. Protein Binding 50%
References	[1]. Bockstaele, Betaxolol, a selective beta(1)-adrenergic receptor antagonist, diminishes anxiety-like behavior during early withdrawal from chronic cocaine administration in rats. Prog Neuropsychopharmacol Biol Psychiatry. 2007 Jun 30;31(5):1119-29. [2]. Comparison of ophthalmic beta-blocking agents. Clin Pharm, 1987. 6(6): p. 451-63.
Additional Infomation	Betaxolol is a propanolamine that is 3-aminopropane-1,2-diol in which the hydrogen of the primary hydoxy is substituted by a 4-[2-(cyclopropylmethoxy)ethyl]phenyl group and one of the hydrogens attached to the amino group is substituted by isopropyl. It is a selective beta1-receptor blocker and is used in the treatment of glaucoma as well as hypertension, arrhythmias, and coronary heart disease. It is also used to reduce non-fatal cardiac events in patients with heart failure. It has a role as a beta-adrenergic antagonist, an antihypertensive agent and a sympatholytic agent. A cardioselective beta-1-adrenergic antagonist with no partial agonist activity. Betaxolol is a beta-Adrenergic Blocker. The mechanism of action of betaxolol is as an Adrenergic beta-Antagonist. Betaxolol is a cardioselective beta-blocker used in the treatment of hypertension. Betaxolol has not been linked to instances of clinically apparent drug induced liver injury. Betaxolol is a racemic mixture and selective beta-1 adrenergic receptor antagonist with antihypertensive and anti-glaucoma activities and devoid of intrinsic sympathomimetic activity. Betaxolol selectively and competitively binds to and blocks beta-1 adrenergic receptors in the heart, thereby decreasing cardiac contractility and rate. This leads to a reduction in cardiac output and lowers blood pressure. When applied topically in the eye, this agent reduces aqueous humor secretion and lowers the intraocular pressure (IOP). In addition, betaxolol prevents the release of renin, a hormone secreted by the kidneys that causes constriction of blood vessels. A cardioselective beta-1-adrenergic antagonist with no partial agonist activity. See also: Betaxolol Hydrochloride (has salt form). Drug Indication For the management of hypertension. FDA Label Mechanism of Action Betaxolol selectively blocks catecholamine stimulation of beta(1)-adrenergic receptors in the heart and vascular smooth muscle. This results in a reduction of heart rate, cardiac output, systolic and diastolic blood pressure, and possibly reflex orthostatic hypotension. Betaxolol can also competitively block beta(2)-adrenergic responses in the bronchial and vascular smooth muscles, causing bronchospasm. Pharmacodynamics Betaxolol is a competitive, beta(1)-selective (cardioselective) adrenergic antagonist. Betaxolol is used to treat hypertension, arrhythmias, coronary heart disease, glaucoma, and is also used to reduce non-fatal cardiac events in patients with heart failure. Activation of beta(1)-receptors (located mainly in the heart) by epinephrine increases the heart rate and the blood pressure, and the heart consumes more oxygen. Drugs such as betaxolol that block these receptors therefore have the reverse effect: they lower the heart rate and blood pressure and hence are used in conditions when the heart itself is deprived of oxygen. They are routinely prescribed in patients with ischemic heart disease. In addition, beta(1)-selective blockers prevent the release of renin, which is a hormone produced by the kidneys which leads to constriction of blood vessels. Betaxolol is lipophilic and exhibits no intrinsic sympathomimetic activity (ISA) or membrane stabilizing activity.

Solubility Data

Solubility (In Vitro)

DMSO: 62~100 mg/mL (201.7~325.3 mM) Water: <1 mg/mL Ethanol: ~62 mg/mL (~201.7 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.5 mg/mL (8.13 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 25.0 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: ≥ 2.5 mg/mL (8.13 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 25.0 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: ≥ 2.5 mg/mL (8.13 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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	3.2528 mL	16.2639 mL	32.5277 mL
	5 mM	0.6506 mL	3.2528 mL	6.5055 mL
	10 mM	0.3253 mL	1.6264 mL	3.2528 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.