Identification

Name
Probucol
Accession Number
DB01599
Type
Small Molecule
Groups
Approved, Investigational
Description

A drug used to lower LDL and HDL cholesterol yet has little effect on serum-triglyceride or VLDL cholesterol. (From Martindale, The Extra Pharmacopoeia, 30th ed, p993).

Structure
Thumb
Synonyms
  • 4,4'- (Isopropylidenedithio)bis(2,6-di-tert-butylphenol)
  • Acetone bis(3,5-di-tert-butyl-4-hydroxyphenyl) mercaptole
  • Biphenabid
  • Bisbid
  • Bisphenabid
  • Probucol
  • Probucolum
External IDs
DH-581
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
LorelcoTablet250 mgOralSanofi Aventis1995-12-312009-04-03Canada
International/Other Brands
Lesterol / Lorelco / Lurselle / Serterol / Sinlestal / Superlipid
Categories
UNII
P3CTH044XJ
CAS number
23288-49-5
Weight
Average: 516.842
Monoisotopic: 516.30957216
Chemical Formula
C31H48O2S2
InChI Key
FYPMFJGVHOHGLL-UHFFFAOYSA-N
InChI
InChI=1S/C31H48O2S2/c1-27(2,3)21-15-19(16-22(25(21)32)28(4,5)6)34-31(13,14)35-20-17-23(29(7,8)9)26(33)24(18-20)30(10,11)12/h15-18,32-33H,1-14H3
IUPAC Name
2,6-di-tert-butyl-4-({2-[(3,5-di-tert-butyl-4-hydroxyphenyl)sulfanyl]propan-2-yl}sulfanyl)phenol
SMILES
CC(C)(SC1=CC(=C(O)C(=C1)C(C)(C)C)C(C)(C)C)SC1=CC(=C(O)C(=C1)C(C)(C)C)C(C)(C)C

Pharmacology

Indication

Used to lower LDL and HDL cholesterol.

Structured Indications
Not Available
Pharmacodynamics

Probucol lowers the level of cholesterol in the bloodstream by increasing the rate of LDL catabolism. Additionally, probucol may inhibit cholesterol synthesis and delay cholesterol absorption. Probucol is a powerful antioxidant drug normally used to prevent vascular disease caused by the free radicals in the body.

Mechanism of action

Probucol lowers serum cholesterol by increasing the fractional rate of low-density lipoprotein (LDL) catabolism in the final metabolic pathway for cholesterol elimination from the body. Additionally, probucol may inhibit early stages of cholesterol biosynthesis and slightly inhibit dietary cholesterol absorption. Recent information suggests that probucol may inhibit the oxidation and tissue deposition of LDL cholesterol, thereby inhibiting atherogenesis. It appears to inhibits ABCA1-mediated cellular lipid efflux.

TargetActionsOrganism
AATP-binding cassette sub-family A member 1
inhibitor
Human
ULiver carboxylesterase 1Not AvailableHuman
Absorption

Absorption from the gastrointestinal tract is limited and variable (about 7%).

Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life

Ranges from 12 hours to more than 500 hours, the longest half-life probably being in adipose tissue.

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

Interactions

Drug Interactions
DrugInteractionDrug group
MacimorelinProbucol may increase the QTc-prolonging activities of Macimorelin.Approved, Investigational
RibociclibThe risk or severity of QTc prolongation can be increased when Ribociclib is combined with Probucol.Approved
Food Interactions
  • Take with food. Food increases availability.

References

Synthesis Reference

Claudio Giordano, Giuseppe Barreca, "Process for preparing an intermediate useful in the syntheis of probucol." U.S. Patent US5157156, issued July, 1988.

US5157156
General References
Not Available
External Links
Human Metabolome Database
HMDB15537
KEGG Drug
D00476
KEGG Compound
C07373
PubChem Compound
4912
PubChem Substance
46508876
ChemSpider
4743
BindingDB
50007260
ChEBI
8427
ChEMBL
CHEMBL608
Therapeutic Targets Database
DAP000916
PharmGKB
PA451107
Drugs.com
Drugs.com Drug Page
Wikipedia
Probucol
ATC Codes
C10AX02 — Probucol

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedSupportive CareHealthy Volunteers1
1, 2Not Yet RecruitingPreventionAge-Related Cognitive Decline / Dementia of the Alzheimer's Type / Mild Cognitive Impairment Due to Alzheimer's Disease1
2CompletedTreatmentDiabetic Nephropathies1
2Unknown StatusTreatmentPeripheral Artery Disease (PAD)1
3CompletedTreatmentHyperlipidemias1
4Active Not RecruitingPreventionIntracranial Hemorrhages / Ischemia, Brain1
4Active Not RecruitingTreatmentIntracranial Hemorrhages / Ischemia, Brain1
4CompletedHealth Services ResearchHealthy Volunteers1
4CompletedTreatmentArteriosclerosis Obliterans / Type 2 Diabetes Mellitus1
4CompletedTreatmentDiabetic Nephropathies1
4CompletedTreatmentGlomerulonephritis / IgA Nephropathy1
4CompletedTreatmentHealthy Volunteers1
4RecruitingTreatmentSevere Hypercholesterolemia1
Not AvailableActive Not RecruitingTreatmentRenal Dysfunction / Type 2 Diabetes Mellitus1
Not AvailableCompletedNot AvailableChinese Healthy Volunteers1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Dosage forms
FormRouteStrength
TabletOral250 mg
Prices
Unit descriptionCostUnit
Probucol powder2.45USD g
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)125 °CPhysProp
Predicted Properties
PropertyValueSource
Water Solubility4.18e-05 mg/mLALOGPS
logP8.92ALOGPS
logP10.57ChemAxon
logS-7.1ALOGPS
pKa (Strongest Acidic)10.29ChemAxon
pKa (Strongest Basic)-5.1ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area40.46 Å2ChemAxon
Rotatable Bond Count8ChemAxon
Refractivity159.26 m3·mol-1ChemAxon
Polarizability62.35 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.992
Blood Brain Barrier+0.8118
Caco-2 permeable+0.778
P-glycoprotein substrateNon-substrate0.6117
P-glycoprotein inhibitor INon-inhibitor0.8088
P-glycoprotein inhibitor IINon-inhibitor0.8381
Renal organic cation transporterNon-inhibitor0.868
CYP450 2C9 substrateNon-substrate0.6651
CYP450 2D6 substrateNon-substrate0.6765
CYP450 3A4 substrateSubstrate0.5288
CYP450 1A2 substrateNon-inhibitor0.8029
CYP450 2C9 inhibitorNon-inhibitor0.8098
CYP450 2D6 inhibitorNon-inhibitor0.9232
CYP450 2C19 inhibitorNon-inhibitor0.7852
CYP450 3A4 inhibitorNon-inhibitor0.7851
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.8793
Ames testNon AMES toxic0.9398
CarcinogenicityNon-carcinogens0.6603
BiodegradationNot ready biodegradable1.0
Rat acute toxicity1.9829 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9868
hERG inhibition (predictor II)Non-inhibitor0.7771
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

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 phenylpropanes. These are organic compounds containing a phenylpropane moiety.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Phenylpropanes
Direct Parent
Phenylpropanes
Alternative Parents
Thiophenol ethers / Phenols / Dithioketals / Alkylarylthioethers / Sulfenyl compounds / Organooxygen compounds / Hydrocarbon derivatives
Substituents
Phenylpropane / Aryl thioether / Thiophenol ether / Alkylarylthioether / Phenol / Dithioketal / Thioacetal / Sulfenyl compound / Thioether / Organic oxygen compound
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
polyphenol, dithioketal (CHEBI:8427)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Syntaxin binding
Specific Function
cAMP-dependent and sulfonylurea-sensitive anion transporter. Key gatekeeper influencing intracellular cholesterol transport.
Gene Name
ABCA1
Uniprot ID
O95477
Uniprot Name
ATP-binding cassette sub-family A member 1
Molecular Weight
254299.89 Da
References
  1. Favari E, Zanotti I, Zimetti F, Ronda N, Bernini F, Rothblat GH: Probucol inhibits ABCA1-mediated cellular lipid efflux. Arterioscler Thromb Vasc Biol. 2004 Dec;24(12):2345-50. Epub 2004 Oct 28. [PubMed:15514211]
  2. Yamamoto A: A uniqe antilipidemic drug--probucol. J Atheroscler Thromb. 2008 Dec;15(6):304-5. Epub 2008 Dec 11. [PubMed:19075491]
  3. de la Llera-Moya M, Drazul-Schrader D, Asztalos BF, Cuchel M, Rader DJ, Rothblat GH: The ability to promote efflux via ABCA1 determines the capacity of serum specimens with similar high-density lipoprotein cholesterol to remove cholesterol from macrophages. Arterioscler Thromb Vasc Biol. 2010 Apr;30(4):796-801. doi: 10.1161/ATVBAHA.109.199158. Epub 2010 Jan 14. [PubMed:20075420]
  4. Sirtori CR, Manzoni C, Lovati MR: Mechanisms of lipid-lowering agents. Cardiology. 1991;78(3):226-35. [PubMed:1868500]
  5. Shichiri M, Takanezawa Y, Rotzoll DE, Yoshida Y, Kokubu T, Ueda K, Tamai H, Arai H: ATP-binding cassette transporter A1 is involved in hepatic alpha-tocopherol secretion. J Nutr Biochem. 2010 May;21(5):451-6. doi: 10.1016/j.jnutbio.2009.02.002. Epub 2009 May 7. [PubMed:19427182]
  6. Arakawa R, Tsujita M, Iwamoto N, Ito-Ohsumi C, Lu R, Wu CA, Shimizu K, Aotsuka T, Kanazawa H, Abe-Dohmae S, Yokoyama S: Pharmacological inhibition of ABCA1 degradation increases HDL biogenesis and exhibits antiatherogenesis. J Lipid Res. 2009 Nov;50(11):2299-305. doi: 10.1194/jlr.M900122-JLR200. Epub 2009 May 20. [PubMed:19458386]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Triglyceride lipase activity
Specific Function
Involved in the detoxification of xenobiotics and in the activation of ester and amide prodrugs. Hydrolyzes aromatic and aliphatic esters, but has no catalytic activity toward amides or a fatty acy...
Gene Name
CES1
Uniprot ID
P23141
Uniprot Name
Liver carboxylesterase 1
Molecular Weight
62520.62 Da
References
  1. Jeon SM, Park YB, Kwon OS, Huh TL, Lee WH, Do KM, Park T, Choi MS: Vitamin E supplementation alters HDL-cholesterol concentration and paraoxonase activity in rabbits fed high-cholesterol diet: comparison with probucol. J Biochem Mol Toxicol. 2005;19(5):336-46. [PubMed:16292755]

Drug created on August 29, 2007 12:43 / Updated on November 09, 2017 03:02