Identification

Name
Arotinolol
Accession Number
DB09204
Type
Small Molecule
Groups
Investigational
Description

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.[6] Artinolol is being developed by Sumitomo Pharmaceutical Co., Ltd. and it is currently under clinical trials.[10]

Structure
Thumb
Synonyms
Not Available
External IDs
S-596
International/Other Brands
Almarl
Categories
UNII
394E3P3B99
CAS number
68377-92-4
Weight
Average: 371.53
Monoisotopic: 371.07959045
Chemical Formula
C15H21N3O2S3
InChI Key
BHIAIPWSVYSKJS-UHFFFAOYSA-N
InChI
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)
IUPAC Name
5-(2-{[3-(tert-butylamino)-2-hydroxypropyl]sulfanyl}-1,3-thiazol-4-yl)thiophene-2-carboxamide
SMILES
CC(C)(C)NCC(O)CSC1=NC(=CS1)C1=CC=C(S1)C(N)=O

Pharmacology

Indication

Artinolol was introduced to be used as an antihypertensive agent since 1986.[7] 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.[10]

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.[6]

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.[6]

TargetActionsOrganism
ABeta-1 adrenergic receptor
antagonist
Human
ABeta-2 adrenergic receptor
antagonist
Human
AAlpha-1 adrenergic receptors
antagonist
Human
Absorption

Arotinolol gets rapidly absorbed and distributed in the plasma. The plasma concentration peaks 2 hours after initial administration.[5]

Volume of distribution

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.[8]

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.[8]

Metabolism

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.[6]

Route of elimination

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.[6]

Half life

The reported half-life of arotinolol is 7.2 hours.[6]

Clearance
Not Available
Toxicity

The major toxic effects reported for arotinolol-like drugs are the presence of central nervous system depression.[9]

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(4R)-limonene(4R)-limonene may decrease the antihypertensive activities of Arotinolol.
1,10-Phenanthroline1,10-Phenanthroline may increase the bradycardic activities of Arotinolol.
4-Methoxyamphetamine4-Methoxyamphetamine may increase the atrioventricular blocking (AV block) activities of Arotinolol.
AcebutololThe risk or severity of adverse effects can be increased when Arotinolol is combined with Acebutolol.
AceclofenacAceclofenac may decrease the antihypertensive activities of Arotinolol.
AcemetacinAcemetacin may decrease the antihypertensive activities of Arotinolol.
AcepromazineArotinolol may increase the orthostatic hypotensive activities of Acepromazine.
AceprometazineAceprometazine may increase the hypotensive activities of Arotinolol.
AcetaminophenAcetaminophen may decrease the excretion rate of Arotinolol which could result in a higher serum level.
AcetohexamideArotinolol may increase the hypoglycemic activities of Acetohexamide.
Food Interactions
Not Available

References

General References
  1. Zhao J, Golozoubova V, Cannon B, Nedergaard J: Arotinolol is a weak partial agonist on beta 3-adrenergic receptors in brown adipocytes. Can J Physiol Pharmacol. 2001 Jul;79(7):585-93. [PubMed:11478592]
  2. Lee KS, Kim JS, Kim JW, Lee WY, Jeon BS, Kim D: A multicenter randomized crossover multiple-dose comparison study of arotinolol and propranolol in essential tremor. Parkinsonism Relat Disord. 2003 Aug;9(6):341-7. [PubMed:12853233]
  3. Wu H, Zhang Y, Huang J, Zhang Y, Liu G, Sun N, Yu Z, Zhou Y: Clinical trial of arotinolol in the treatment of hypertension: dippers vs. non-dippers. Hypertens Res. 2001 Sep;24(5):605-10. [PubMed:11675958]
  4. Miyauchi E, Matsumoto M, Kimura Y, Hattori H, Tsukio Y, Tsuchiya H, Takasaki M, Munehira J, Yamada K, Iwai K, Kawanishi K, Hoshino T, Murai H: [Clinical effect of arotinolol hydrochloride and its influence on renal function in elderly patients with essential hypertension]. Nihon Ronen Igakkai Zasshi. 1999 Aug;36(8):542-6. [PubMed:10554561]
  5. Nakashima M, Uematsu T, Takiguchi Y, Hashimoto H, Watanabe I, Morioka S, Hibino T: Effect of ophthalmic administration of S-596 (Arotinolol) on intraocular pressure and haemodynamics in health volunteers: comparison with timolol. Eur J Clin Pharmacol. 1985;28(4):391-6. [PubMed:2411566]
  6. Ganten D. and Mulrow P.J. (1990). Pharmacology of anti-hypertensive therapeutics (1st ed.). Springer .
  7. Allen R. (1988). Annual reports in medicinal chemistry (23rd ed.). Academic press.
  8. Kato R., Estabrook W. and Cayen M. (1988). Xenobiotic metabolism and disposition (2nd ed.). Taylor and Francis.
  9. Pillay V.V. (2013). Modern medical toxicology (4th ed.). Jaypee Brothers.
  10. Clinical trials [Link]
External Links
KEGG Drug
D07465
PubChem Compound
2239
PubChem Substance
310265112
ChemSpider
2152
BindingDB
81885
ChEBI
135569
ChEMBL
CHEMBL93298
Wikipedia
Arotinolol
MSDS
Download (231 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Active Not RecruitingTreatmentChronic Kidney Disease (CKD)1
4RecruitingTreatmentHypertension,Essential1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)149-153ºC'MSDS'
boiling point (°C)599ºC at 760 mmHg'MSDS'
water solubilitySlightly solubleOfficial Monographs for Pharmacology part I.
logP2.3'MSDS'
Predicted Properties
PropertyValueSource
Water Solubility0.0225 mg/mLALOGPS
logP2.38ALOGPS
logP2.54ChemAxon
logS-4.2ALOGPS
pKa (Strongest Acidic)13.51ChemAxon
pKa (Strongest Basic)9.84ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area88.24 Å2ChemAxon
Rotatable Bond Count8ChemAxon
Refractivity96.71 m3·mol-1ChemAxon
Polarizability40.66 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as thiophene carboxamides. These are compounds containing a thiophene ring which bears a carboxamide.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Thiophenes
Sub Class
Thiophene carboxylic acids and derivatives
Direct Parent
Thiophene carboxamides
Alternative Parents
2-heteroaryl carboxamides / Alkylarylthioethers / 2,5-disubstituted thiophenes / 2,4-disubstituted thiazoles / Heteroaromatic compounds / Secondary alcohols / Primary carboxylic acid amides / Amino acids and derivatives / 1,2-aminoalcohols / Sulfenyl compounds
show 5 more
Substituents
2-heteroaryl carboxamide / Aryl thioether / Thiophene carboxamide / 2,4-disubstituted 1,3-thiazole / Alkylarylthioether / 2,5-disubstituted thiophene / Azole / Heteroaromatic compound / Thiazole / 1,2-aminoalcohol
show 21 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Receptor signaling protein activity
Specific Function
Beta-adrenergic receptors mediate the catecholamine-induced activation of adenylate cyclase through the action of G proteins. This receptor binds epinephrine and norepinephrine with approximately e...
Gene Name
ADRB1
Uniprot ID
P08588
Uniprot Name
Beta-1 adrenergic receptor
Molecular Weight
51322.1 Da
References
  1. Ganten D. and Mulrow P.J. (1990). Pharmacology of anti-hypertensive therapeutics (1st ed.). Springer .
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Protein homodimerization activity
Specific Function
Beta-adrenergic receptors mediate the catecholamine-induced activation of adenylate cyclase through the action of G proteins. The beta-2-adrenergic receptor binds epinephrine with an approximately ...
Gene Name
ADRB2
Uniprot ID
P07550
Uniprot Name
Beta-2 adrenergic receptor
Molecular Weight
46458.32 Da
References
  1. Ganten D. and Mulrow P.J. (1990). Pharmacology of anti-hypertensive therapeutics (1st ed.). Springer .
Kind
Protein group
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Protein heterodimerization activity
Specific Function
This alpha-adrenergic receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. Its effect is mediated by G(q) and G(11) prot...

Components:
References
  1. Ganten D. and Mulrow P.J. (1990). Pharmacology of anti-hypertensive therapeutics (1st ed.). Springer .

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. Iwaki M, Niwa T, Bandoh S, Itoh M, Hirose H, Kawase A, Komura H: Application of substrate depletion assay to evaluation of CYP isoforms responsible for stereoselective metabolism of carvedilol. Drug Metab Pharmacokinet. 2016 Dec;31(6):425-432. doi: 10.1016/j.dmpk.2016.08.007. Epub 2016 Sep 2. [PubMed:27836712]
  2. Brodde OE, Kroemer HK: Drug-drug interactions of beta-adrenoceptor blockers. Arzneimittelforschung. 2003;53(12):814-22. [PubMed:14732961]
  3. Sternieri E, Coccia CP, Pinetti D, Guerzoni S, Ferrari A: Pharmacokinetics and interactions of headache medications, part II: prophylactic treatments. Expert Opin Drug Metab Toxicol. 2006 Dec;2(6):981-1007. doi: 10.1517/17425255.2.6.981 . [PubMed:17125412]

Carriers

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. Kato R., Estabrook W. and Cayen M. (1988). Xenobiotic metabolism and disposition (2nd ed.). Taylor and Francis.
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Not Available
Specific Function
Functions as transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in...
Gene Name
ORM1
Uniprot ID
P02763
Uniprot Name
Alpha-1-acid glycoprotein 1
Molecular Weight
23511.38 Da
References
  1. Kato R., Estabrook W. and Cayen M. (1988). Xenobiotic metabolism and disposition (2nd ed.). Taylor and Francis.

Drug created on October 19, 2015 13:52 / Updated on October 01, 2018 14:48