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Identification
NameMevastatin
Accession NumberDB06693
TypeSmall Molecule
GroupsExperimental
Description

Mevastatin or compactin is a cholesterol-lowering agent isolated from Penicillium citinium. It was the first discovered agent belonging to the class of cholesterol-lowering medications known as statins. During a search for antibiotic compounds produced by fungi in 1971, Akira Endo at Sankyo Co. (Japan) discovered a class of compounds that appeared to lower plasma cholesterol levels. Two years later, the research group isolated a compound structurally similar to hydroxymethylglutarate (HMG) that inhibited the incorporation of acetate. The compound was proposed to bind to the reductase enzyme and was named compactin. Mevastatin is a competitive inhibitor of HMG-Coenzyme A (HMG-CoA) reductase with a binding affinity 10,000 times greater than the HMG-CoA substrate itself. Mevastatin is a pro-drug that is activated by in vivo hydrolysis of the lactone ring. It has served as one of the lead compounds for the development of the synthetic compounds used today.

Structure
Thumb
Synonyms
SynonymLanguageCode
CompactinNot AvailableNot Available
Prescription ProductsNot Available
Generic Prescription ProductsNot Available
Over the Counter ProductsNot Available
International BrandsNot Available
Brand mixturesNot Available
SaltsNot Available
Categories
CAS number73573-88-3
WeightAverage: 408.5283
Monoisotopic: 408.251188884
Chemical FormulaC23H36O6
InChI KeyBOZILQFLQYBIIY-INTXDZFKSA-N
InChI
InChI=1S/C23H36O6/c1-4-14(2)23(28)29-20-7-5-6-16-9-8-15(3)19(22(16)20)11-10-17(24)12-18(25)13-21(26)27/h6,8-9,14-15,17-20,22,24-25H,4-5,7,10-13H2,1-3H3,(H,26,27)/t14-,15-,17+,18+,19-,20-,22-/m0/s1
IUPAC Name
(3R,5R)-7-[(1S,2S,8S,8aR)-2-methyl-8-{[(2S)-2-methylbutanoyl]oxy}-1,2,6,7,8,8a-hexahydronaphthalen-1-yl]-3,5-dihydroxyheptanoic acid
SMILES
[H][C@@](O)(CC[C@@]1([H])[C@@]([H])(C)C=CC2=CCC[C@]([H])(OC(=O)[C@@]([H])(C)CC)[C@]12[H])C[C@@]([H])(O)CC(O)=O
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as carbocyclic fatty acids. These are fatty acids containing a carbocylic ring .
KingdomOrganic compounds
Super ClassLipids and lipid-like molecules
ClassFatty Acyls
Sub ClassFatty acids and conjugates
Direct ParentCarbocyclic fatty acids
Alternative Parents
Substituents
  • Medium-chain hydroxy acid
  • Fatty alcohol
  • Carbocyclic fatty acid
  • Medium-chain fatty acid
  • Fatty acid ester
  • Branched fatty acid
  • Beta-hydroxy acid
  • Hydroxy acid
  • Dicarboxylic acid or derivatives
  • Secondary alcohol
  • Carboxylic acid ester
  • Carboxylic acid
  • Carboxylic acid derivative
  • Hydrocarbon derivative
  • Organooxygen compound
  • Carbonyl group
  • Alcohol
  • Aliphatic homopolycyclic compound
Molecular FrameworkAliphatic homopolycyclic compounds
External DescriptorsNot Available
Pharmacology
IndicationNot used therapeutically due to its many side effects.
PharmacodynamicsThe primary cause of cardiovascular disease is atherosclerotic plaque formation. Sustained elevations of cholesterol in the blood increase the risk of cardiovascular disease. Mevastatin lowers hepatic production of cholesterol by competitively inhibiting HMG-CoA reductase, the enzyme that catalyzes the rate-limiting step in the cholesterol biosynthesis pathway via the mevalonic acid pathway. Decreased hepatic cholesterol levels causes increased uptake of low density lipoprotein (LDL) cholesterol and reduces cholesterol levels in the circulation.
Mechanism of actionMevastatin is structurally similar to the HMG, a substituent of the endogenous substrate of HMG-CoA reductase. Mevastatin is a prodrug that is activated in vivo via hydrolysis of the lactone ring. The hydrolyzed lactone ring mimics the tetrahedral intermediate produced by the reductase allowing the agent to bind with 10,000 times greater affinity than its natural substrate. The bicyclic portion of mevastatin binds to the coenzyme A portion of the active site.
AbsorptionNot Available
Volume of distributionNot Available
Protein bindingNot Available
Metabolism
Route of eliminationNot Available
Half lifeNot Available
ClearanceNot Available
ToxicitySide effects include those of other statins, such as myalgias, abdominal pain, nausea. It also has a higher chance of giving more severe side effects related to myotoxicity (myopathy, myositis, rhabdomyolysis), and hepatotoxicity, than other statins. Due to these major side effects and their enhanced rate of occurance, Mevastatin is not given therapeutically.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9714
Blood Brain Barrier+0.639
Caco-2 permeable-0.6631
P-glycoprotein substrateSubstrate0.7964
P-glycoprotein inhibitor INon-inhibitor0.8324
P-glycoprotein inhibitor IIInhibitor0.6601
Renal organic cation transporterNon-inhibitor0.8617
CYP450 2C9 substrateNon-substrate0.8503
CYP450 2D6 substrateNon-substrate0.9115
CYP450 3A4 substrateSubstrate0.7206
CYP450 1A2 substrateNon-inhibitor0.8952
CYP450 2C9 substrateNon-inhibitor0.8909
CYP450 2D6 substrateNon-inhibitor0.8903
CYP450 2C19 substrateNon-inhibitor0.8513
CYP450 3A4 substrateInhibitor0.6571
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.7992
Ames testNon AMES toxic0.8927
CarcinogenicityNon-carcinogens0.9523
BiodegradationNot ready biodegradable0.8854
Rat acute toxicity2.6058 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8359
hERG inhibition (predictor II)Non-inhibitor0.6699
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage formsNot Available
PricesNot Available
PatentsNot Available
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point152 °CPhysProp
logP3.95SANGSTER (1994)
Predicted Properties
PropertyValueSource
Water Solubility0.0798 mg/mLALOGPS
logP4.03ALOGPS
logP2.95ChemAxon
logS-3.7ALOGPS
pKa (Strongest Acidic)4.21ChemAxon
pKa (Strongest Basic)-2.7ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area104.06 Å2ChemAxon
Rotatable Bond Count11ChemAxon
Refractivity112.13 m3·mol-1ChemAxon
Polarizability45.31 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis Reference

Scott Primrose, David King, Ed Yaworski, Jayaramaiyer Radhakrishnan, David He, Xinfa Xiao, “Fermentation process for preparation of compactin.” U.S. Patent US5691173, issued September, 1977.

US5691173
General Reference

Chemspider

Pubchem

External Links
ATC CodesNot Available
AHFS Codes
  • 24:06.08
PDB EntriesNot Available
FDA labelNot Available
MSDSNot Available
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available

Targets

1. 3-hydroxy-3-methylglutaryl-coenzyme A reductase

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
3-hydroxy-3-methylglutaryl-coenzyme A reductase P04035 Details

References:

  1. Kocarek TA, Dahn MS, Cai H, Strom SC, Mercer-Haines NA: Regulation of CYP2B6 and CYP3A expression by hydroxymethylglutaryl coenzyme A inhibitors in primary cultured human hepatocytes. Drug Metab Dispos. 2002 Dec;30(12):1400-5. Pubmed
  2. Cenedella RJ, Kuszak JR, Al-Ghoul KJ, Qin S, Sexton PS: Discordant expression of the sterol pathway in lens underlies simvastatin-induced cataracts in Chbb: Thom rats. J Lipid Res. 2003 Jan;44(1):198-211. Pubmed
  3. Stoebner PE, Michot C, Ligeron C, Durand L, Meynadier J, Meunier L: [Simvastatin-induced lichen planus pemphigoides] Ann Dermatol Venereol. 2003 Feb;130(2 Pt 1):187-90. Pubmed
  4. Pappu AS, Bacon SP, Illingworth DR: Residual effects of lovastatin and simvastatin on urinary mevalonate excretions in patients with familial hypercholesterolemia. J Lab Clin Med. 2003 Apr;141(4):250-6. Pubmed
  5. Liu L, Zhang R, Zhao JJ, Rogers JD, Hsieh JY, Fang W, Matuszewski BK, Dobrinska MR: Determination of simvastatin-derived HMG-CoA reductase inhibitors in biomatrices using an automated enzyme inhibition assay with radioactivity detection. J Pharm Biomed Anal. 2003 Apr 24;32(1):107-23. Pubmed
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  7. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. Pubmed

Enzymes

1. Liver carboxylesterase 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Liver carboxylesterase 1 P23141 Details

References:

  1. Fleming CD, Bencharit S, Edwards CC, Hyatt JL, Tsurkan L, Bai F, Fraga C, Morton CL, Howard-Williams EL, Potter PM, Redinbo MR: Structural insights into drug processing by human carboxylesterase 1: tamoxifen, mevastatin, and inhibition by benzil. J Mol Biol. 2005 Sep 9;352(1):165-77. Pubmed

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Drug created on March 13, 2010 15:07 / Updated on September 16, 2013 18:04