Identification

Name
Celiprolol
Accession Number
DB04846
Type
Small Molecule
Groups
Approved, Investigational
Description

Celiprolol is indicated for the management of mild to moderate hypertension and effort-induced angina pectoris. It has a unique pharmacology: it is a selective β1 receptor antagonist, but a β2 receptor partial agonist. It is also a weak α2 receptor antagonist. In 2010 a clinical trial has suggested a use for this medication in the prevention of vascular complications of a rare inherited disease called vascular Ehlers–Danlos syndrome. This study demonstrated decreased incidence of arterial rupture or dissection (a specific type of arterial rupture in which the layers of the vessel separate prior to complete failure of the artery wall). Celiprolol is not approved for use by the FDA in the treatment of vascular Ehlers–Danlos syndrome.

Structure
Thumb
Synonyms
  • RS)-N'-{3-acetyl-4-[3-(tert-butylamino)-2-hydroxypropoxy]phenyl}-N,N-diethylurea
External IDs
REV 5320 A / ST 1396 / UL/1677
International/Other Brands
Cardem / Celipres / Celipro / Celol / Cordiax / Dilanorm / Selectol (Sanofi)
Categories
UNII
DRB57K47QC
CAS number
56980-93-9
Weight
Average: 379.501
Monoisotopic: 379.247106555
Chemical Formula
C20H33N3O4
InChI Key
JOATXPAWOHTVSZ-UHFFFAOYSA-N
InChI
InChI=1S/C20H33N3O4/c1-7-23(8-2)19(26)22-15-9-10-18(17(11-15)14(3)24)27-13-16(25)12-21-20(4,5)6/h9-11,16,21,25H,7-8,12-13H2,1-6H3,(H,22,26)
IUPAC Name
1-{3-acetyl-4-[3-(tert-butylamino)-2-hydroxypropoxy]phenyl}-3,3-diethylurea
SMILES
CCN(CC)C(=O)NC1=CC=C(OCC(O)CNC(C)(C)C)C(=C1)C(C)=O

Pharmacology

Indication

Celiprolol is indicated for the management of mild to moderate hypertension and effort-induced angina pectoris.

Pharmacodynamics
Not Available
Mechanism of action

Celiprolol is a vasoactive beta-1 selective adrenoceptor antagonist with partial beta-2 agonist activity. The beta-2 agonist activity is thought to account for its mild vasodilating properties. It lowers blood pressure in hypertensive patients at rest and on exercise. The effects on heart rate and cardiac output are dependent on the pre-existing background level of sympathetic tone. Under conditions of stress such as exercise, celiprolol attenuates chronotropic and inotropic responses to sympathetic stimulation. However, at rest minimal impairment of cardiac function is seen.

TargetActionsOrganism
ABeta-1 adrenergic receptor
antagonist
Human
ABeta-2 adrenergic receptor
agonist
Human
UBeta-3 adrenergic receptor
agonist
Human
UAlpha-2A adrenergic receptor
antagonist
Human
UAlpha-2B adrenergic receptor
antagonist
Human
UAlpha-2C adrenergic receptor
antagonist
Human
Absorption

Absorption of an oral dose is rapid and consistent but incomplete (55% for 200 mg dose and 74% for 400 mg dose) from the gastrointestinal tract. The bioavailability of celiprolol has been shown to be markedly affected by food and one should avoid administration of celiprolol with food. Coadministration of chlorthalidone, hydrochlorothiazide and theophylline also reduces the bioavailability of celiprolol. Following oral dosing, maximal blood concentrations are reached between 2 and 3 hours.

Volume of distribution

The distribution volume is 4.5L/kg. Celiprolol is hydrophilic and does not cross the blood-brain barrier. The binding to plasma proteins is about 25-30%.

Protein binding

25-30%.

Metabolism

A 14C labelled dose was completely recovered within 48 hours. The first-pass effect in the liver is insignificant. Celiprolol is metabolized to a minor extent (1-3%).

Route of elimination
Not Available
Half life

5 hours

Clearance

Cleared by both renal and non-renal excretory pathways. Celiprolol is not recommended for patients with creatinine clearance less than 15 mL per minute.

Toxicity

No data are available regarding celiprolol overdose in humans. The most common symptoms to be expected following overdosage with beta-adrenoceptor blocking agents are bradycardia, hypotension, bronchospasm and acute cardiac insufficiency.

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 Celiprolol.
1,10-Phenanthroline1,10-Phenanthroline may increase the bradycardic activities of Celiprolol.
4-Methoxyamphetamine4-Methoxyamphetamine may increase the atrioventricular blocking (AV block) activities of Celiprolol.
7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline may increase the hypotensive activities of Celiprolol.
AbediterolCeliprolol may decrease the bronchodilatory activities of Abediterol.
AcebutololThe therapeutic efficacy of Celiprolol can be decreased when used in combination with Acebutolol.
AceclofenacAceclofenac may decrease the antihypertensive activities of Celiprolol.
AcemetacinThe therapeutic efficacy of Celiprolol can be decreased when used in combination with Acemetacin.
AcepromazineCeliprolol may increase the orthostatic hypotensive activities of Acepromazine.
AceprometazineAceprometazine may increase the hypotensive activities of Celiprolol.
Food Interactions
Not Available

References

Synthesis Reference

Zolss, G., Pittner, H., Stormann-Menninger-Lerchenthal, H. and Lindner, I.; US. Patent 3,983,169; September 28,1976; assigned to Chemie Linz AG (Austria).

General References
  1. Ong KT, Perdu J, De Backer J, Bozec E, Collignon P, Emmerich J, Fauret AL, Fiessinger JN, Germain DP, Georgesco G, Hulot JS, De Paepe A, Plauchu H, Jeunemaitre X, Laurent S, Boutouyrie P: Effect of celiprolol on prevention of cardiovascular events in vascular Ehlers-Danlos syndrome: a prospective randomised, open, blinded-endpoints trial. Lancet. 2010 Oct 30;376(9751):1476-84. doi: 10.1016/S0140-6736(10)60960-9. Epub 2010 Sep 7. [PubMed:20825986]
External Links
KEGG Drug
D07660
PubChem Compound
2663
PubChem Substance
310264853
ChemSpider
2563
ChEBI
94461
ChEMBL
CHEMBL27810
Drugs.com
Drugs.com Drug Page
Wikipedia
Celiprolol
ATC Codes
C07AB08 — Celiprolol
MSDS
Download (80.4 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedTreatmentCHROMOSOME 2q31.2 DELETION SYNDROME / Ehlers-danlos syndrome, type IV, autosomal dominant1
4RecruitingTreatmentChronic Obstructive Pulmonary Disease (COPD)1

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)120-122Zolss, G., Pittner, H., Stormann-Menninger-Lerchenthal, H. and Lindner, I.; US. Patent 3,983,169; September 28,1976; assigned to Chemie Linz AG (Austria).
Predicted Properties
PropertyValueSource
Water Solubility0.174 mg/mLALOGPS
logP2.29ALOGPS
logP1.5ChemAxon
logS-3.3ALOGPS
pKa (Strongest Acidic)13.55ChemAxon
pKa (Strongest Basic)9.66ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area90.9 Å2ChemAxon
Rotatable Bond Count10ChemAxon
Refractivity108.25 m3·mol-1ChemAxon
Polarizability43.18 Å3ChemAxon
Number of Rings1ChemAxon
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 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
LC-MS/MS Spectrum - LC-ESI-QFT , negativeLC-MS/MSsplash10-004i-0039000000-39adbc5dfd1bc8f5b669
LC-MS/MS Spectrum - LC-ESI-QFT , negativeLC-MS/MSsplash10-00kb-0290000000-9ce22ac0f02d4aa4ece7
LC-MS/MS Spectrum - LC-ESI-QFT , negativeLC-MS/MSsplash10-004i-0930000000-fda70a2855a32eef9dfb
LC-MS/MS Spectrum - LC-ESI-QFT , negativeLC-MS/MSsplash10-004i-0910000000-2cd78270a6dd85856f66
LC-MS/MS Spectrum - LC-ESI-QFT , negativeLC-MS/MSsplash10-004i-0900000000-a8bdc80a8e1a59ed7fbc
LC-MS/MS Spectrum - LC-ESI-QFT , negativeLC-MS/MSsplash10-0059-0900000000-854fe31d61307c2c7c53
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-001i-0009000000-1a45fe930a38f058bbf1
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-0pir-2079000000-801b19d8f25b8e4380fa
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-0fk9-9270000000-9c357e3f78ea2c4ad1b7
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-00di-9220000000-fc78f8368ad1492b4a0a
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-00di-9300000000-444019d8fc1a8c096ab8
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-00di-9300000000-87d751e98a384f2697c1

Taxonomy

Description
This compound belongs to the class of organic compounds known as alkyl-phenylketones. These are aromatic compounds containing a ketone substituted by one alkyl group, and a phenyl group.
Kingdom
Organic compounds
Super Class
Organic oxygen compounds
Class
Organooxygen compounds
Sub Class
Carbonyl compounds
Direct Parent
Alkyl-phenylketones
Alternative Parents
N-phenylureas / Acetophenones / Phenoxy compounds / Phenol ethers / Benzoyl derivatives / Aryl alkyl ketones / Alkyl aryl ethers / Ureas / Secondary alcohols / 1,2-aminoalcohols
show 4 more
Substituents
Alkyl-phenylketone / N-phenylurea / Acetophenone / Phenoxy compound / Benzoyl / Aryl alkyl ketone / Phenol ether / Alkyl aryl ether / Monocyclic benzene moiety / Benzenoid
show 15 more
Molecular Framework
Aromatic homomonocyclic 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. Chen X, Minatoguchi S, Arai M, Wang N, Lu C, Narentuoya B, Uno Y, Misao Y, Takemura G, Fujiwara T, Fujiwara H: Celiprolol, a selective beta1-blocker, reduces the infarct size through production of nitric oxide in a rabbit model of myocardial infarction. Circ J. 2007 Apr;71(4):574-9. [PubMed:17384462]
  2. Hayashi T, Juliet PA, Miyazaki-Akita A, Funami J, Matsui-Hirai H, Fukatsu A, Iguchi A: beta1 antagonist and beta2 agonist, celiprolol, restores the impaired endothelial dependent and independent responses and decreased TNFalpha in rat with type II diabetes. Life Sci. 2007 Jan 16;80(6):592-9. Epub 2006 Dec 1. [PubMed:17141277]
  3. Yao EH, Fukuda N, Matsumoto T, Katakawa M, Yamamoto C, Han Y, Ueno T, Kobayashi N, Matsumoto K: Effects of the antioxidative beta-blocker celiprolol on endothelial progenitor cells in hypertensive rats. Am J Hypertens. 2008 Sep;21(9):1062-8. doi: 10.1038/ajh.2008.233. Epub 2008 Jul 17. [PubMed:18636069]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
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. Hayashi T, Juliet PA, Miyazaki-Akita A, Funami J, Matsui-Hirai H, Fukatsu A, Iguchi A: beta1 antagonist and beta2 agonist, celiprolol, restores the impaired endothelial dependent and independent responses and decreased TNFalpha in rat with type II diabetes. Life Sci. 2007 Jan 16;80(6):592-9. Epub 2006 Dec 1. [PubMed:17141277]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Agonist
General Function
Protein homodimerization activity
Specific Function
Beta-adrenergic receptors mediate the catecholamine-induced activation of adenylate cyclase through the action of G proteins. Beta-3 is involved in the regulation of lipolysis and thermogenesis.
Gene Name
ADRB3
Uniprot ID
P13945
Uniprot Name
Beta-3 adrenergic receptor
Molecular Weight
43518.615 Da
References
  1. Nawarskas JJ, Cheng-Lai A, Frishman WH: Celiprolol: A Unique Selective Adrenoceptor Modulator. Cardiol Rev. 2017 Sep/Oct;25(5):247-253. doi: 10.1097/CRD.0000000000000159. [PubMed:28742547]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Antagonist
General Function
Thioesterase binding
Specific Function
Alpha-2 adrenergic receptors mediate the catecholamine-induced inhibition of adenylate cyclase through the action of G proteins. The rank order of potency for agonists of this receptor is oxymetazo...
Gene Name
ADRA2A
Uniprot ID
P08913
Uniprot Name
Alpha-2A adrenergic receptor
Molecular Weight
48956.275 Da
References
  1. Nawarskas JJ, Cheng-Lai A, Frishman WH: Celiprolol: A Unique Selective Adrenoceptor Modulator. Cardiol Rev. 2017 Sep/Oct;25(5):247-253. doi: 10.1097/CRD.0000000000000159. [PubMed:28742547]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Antagonist
General Function
Epinephrine binding
Specific Function
Alpha-2 adrenergic receptors mediate the catecholamine-induced inhibition of adenylate cyclase through the action of G proteins. The rank order of potency for agonists of this receptor is clonidine...
Gene Name
ADRA2B
Uniprot ID
P18089
Uniprot Name
Alpha-2B adrenergic receptor
Molecular Weight
49565.8 Da
References
  1. Nawarskas JJ, Cheng-Lai A, Frishman WH: Celiprolol: A Unique Selective Adrenoceptor Modulator. Cardiol Rev. 2017 Sep/Oct;25(5):247-253. doi: 10.1097/CRD.0000000000000159. [PubMed:28742547]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Antagonist
General Function
Protein homodimerization activity
Specific Function
Alpha-2 adrenergic receptors mediate the catecholamine-induced inhibition of adenylate cyclase through the action of G proteins.
Gene Name
ADRA2C
Uniprot ID
P18825
Uniprot Name
Alpha-2C adrenergic receptor
Molecular Weight
49521.585 Da
References
  1. Nawarskas JJ, Cheng-Lai A, Frishman WH: Celiprolol: A Unique Selective Adrenoceptor Modulator. Cardiol Rev. 2017 Sep/Oct;25(5):247-253. doi: 10.1097/CRD.0000000000000159. [PubMed:28742547]

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. 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]
  2. Brodde OE, Kroemer HK: Drug-drug interactions of beta-adrenoceptor blockers. Arzneimittelforschung. 2003;53(12):814-22. [PubMed:14732961]
  3. 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]

Drug created on October 18, 2007 09:59 / Updated on October 01, 2018 13:56