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Arotinolol (Almarl) is a medication acting as a nonselective α/β-adrenergic receptor blocker and a vasodilating β-blocker. It is an antihypertensive medication used to treat both non-cardiovascular and cardiovascular pathologies.
Physicochemical Properties
| Molecular Formula | C15H21N3O2S3 |
| Molecular Weight | 371.54114 |
| Exact Mass | 371.079 |
| Elemental Analysis | C, 48.49; H, 5.70; N, 11.31; O, 8.61; S, 25.89 |
| CAS # | 68377-92-4 |
| Related CAS # | 87055-50-3 (R-isomer HCl); 68377-92-4; 92075-58-6 (R-isomer); 68377-91-3 (HCl); 101540-26-5 (S-isomer HCl) |
| PubChem CID | 2239 |
| Appearance | Off-white to light yellow solid powder |
| Density | 1.4±0.1 g/cm3 |
| Boiling Point | 599.8±60.0 °C at 760 mmHg |
| Melting Point | 148-149ºC |
| Flash Point | 316.6±32.9 °C |
| Vapour Pressure | 0.0±1.8 mmHg at 25°C |
| Index of Refraction | 1.646 |
| LogP | 2.67 |
| Hydrogen Bond Donor Count | 3 |
| Hydrogen Bond Acceptor Count | 7 |
| Rotatable Bond Count | 8 |
| Heavy Atom Count | 23 |
| Complexity | 406 |
| Defined Atom Stereocenter Count | 0 |
| SMILES | O=C(C1=CC=C(C2=CSC(SCC(O)CNC(C)(C)C)=N2)S1)N |
| InChi Key | BHIAIPWSVYSKJS-UHFFFAOYSA-N |
| InChi Code | InChI=1S/C15H21N3O2S3/c1-15(2,3)17-6-9(19)7-21-14-18-10(8-22-14)11-4-5-12(23-11)13(16)20/h4-5,8-9,17,19H,6-7H2,1-3H3,(H2,16,20) |
| Chemical Name | 5-[2-[3-(tert-butylamino)-2-hydroxypropyl]sulfanyl-1,3-thiazol-4-yl]thiophene-2-carboxamide |
| Synonyms | Arotinolol; Almarl |
| 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 | 5-HT2A Receptor |
| ln Vitro |
Arotinolol demonstrates the selectivity of β-adrenergic receptors as demonstrated by its binding to rat cerebral cortical membranes with pKi values of 9.74 and 9.26 for β1 and β2 adrenoceptors, respectively, in response to 125I-ICYP. There is equal selectivity between β1 and β2[2]. Arotinolol displaces 125I-ICYP binding to 5HT1B-receptors with the pKi values of 7.97 and 8.16, respectively, for β1 and β2 adrenergic receptors, demonstrating its potency for inhibiting the binding of the same radioligand to the 5HT1B-serotonergic receptor site[2]. |
| ln Vivo | Arotinolol (oral gavage; 200 mg/kg; 8 weeks) can dramatically lower PWV and CAP. It can also lessen aortic collagen depositions and enhance arterial stiffness in SHR mice[1]. |
| Animal Protocol |
SHR mice 200 mg/kg Orally gavage; 200 mg/kg; once daily; 8 weeks |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion Arotinolol gets rapidly absorbed and distributed in the plasma. The plasma concentration peaks 2 hours after initial administration. The stereospecificity of arotinolol is very important for its pharmacokinetic characteristics. Both of the enantiomers were found in urine, suggesting this as the major elimination pathway. It is possible to find arotinolol in urine 2-4 hours after initial administration. The stereospecificity of arotinolol is very important for its pharmacokinetic characteristics. The S-enantiomer is highly retained in red blood cells. The distribution studies have shown that arotinolol is mainly distributed from the plasma to the liver followed by the lungs and lastly in the heart. The distribution in the liver was independent on the stereochemistry of the molecules. Metabolism / Metabolites The stereospecificity of arotinolol is very important for its pharmacokinetic characteristics. The R-enantiomer remains unchanged and it is eliminated from the organism by urine in this form while the S-enantiomer is metabolized. Biological Half-Life The reported half-life of arotinolol is 7.2 hours. |
| Toxicity/Toxicokinetics |
Protein Binding The stereospecificity of arotinolol is very important for its pharmacokinetic characteristics. Arotinolol is highly bound to serum proteins reaching a ratio of the original dose of 95.3% in the form of the R-enantiomer and 84.5% of the S-enantiomer. The presented stereospecificity is thought to be related to the α1-acid glycoprotein. |
| References |
[1]. Mechanisms of improved aortic stiffness by arotinolol in spontaneously hypertensive rats.PLoS One. 2014 Feb 12;9(2):e88722. [2]. Characteristics of 1251-lodocyanopindolol Binding to 8-Adrenergic and Serotonin-1B Receptors of Rat Brain: Selectivity of 19-Adrenergic Agents. |
| Additional Infomation |
Arotinolol is a member of thiophenes and an aromatic amide. Arotinolol is an alpha- and beta-receptor blocker developed in Japan. It is a thiopropanolamine with a tertiary butyl moiety. It has been studied for its potential to be an antihypertensive therapy. Artinolol is being developed by Sumitomo Pharmaceutical Co., Ltd. and it is currently under clinical trials. Drug Indication Artinolol was introduced to be used as an antihypertensive agent since 1986. It has been studied for other functions like tremor control for patients with Parkinson disease and it is currently in clinical trials for its use in the control of blood pressure and heart rate. Mechanism of Action Arotinolol binds to the β1-, β2- and α1- adrenergic receptor sites with a very high affinity. Radioligand studies have shown that arotinolol presents a higher affinity to the β-receptor compared to the α-receptor. The elucidated mechanism of action seems to be the result of a reduction in the cardiac output via the β-blockade and an additional inhibition of the counter-regulatory increase in peripheral resistance mediated by the α-blockade. Pharmacodynamics Preclinical studies showed a lack of intrinsic sympathomimetic activities or membrane-establishing properties. It is confirmed that arotinolol presents vasorelaxant activity. This characteristic is also proved to be mainly mediated by its α1-blocking property. In preclinical hypertension trials, there is a specific acute bradycardiac and antihypertensive activity with a pronounced reduction in heart rate. Some reports indicate a delayed development of hypertension when arotinolol is administered daily. Arotinolol has a dose-dependent decrease in cardiac contractility and coronary blood flow as well as an increase in total peripheral resistance. The effects of arotinolol have been confirmed in clinical trials where this drug was able to decrease cardiac index and thus, blood pressure. |
Solubility Data
| Solubility (In Vitro) | DMSO: ~125 mg/mL (~336.4 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (5.60 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 (5.60 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 (5.60 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6915 mL | 13.4575 mL | 26.9150 mL | |
| 5 mM | 0.5383 mL | 2.6915 mL | 5.3830 mL | |
| 10 mM | 0.2692 mL | 1.3458 mL | 2.6915 mL |