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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
Compactin
External Identifiers Not Available
Approved Prescription ProductsNot Available
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
SaltsNot Available
Categories
UNII1UQM1K0W9X
CAS number73573-88-3
WeightAverage: 390.52
Monoisotopic: 390.240624195
Chemical FormulaC23H34O5
InChI KeyAJLFOPYRIVGYMJ-INTXDZFKSA-N
InChI
InChI=1S/C23H34O5/c1-4-14(2)23(26)28-20-7-5-6-16-9-8-15(3)19(22(16)20)11-10-18-12-17(24)13-21(25)27-18/h6,8-9,14-15,17-20,22,24H,4-5,7,10-13H2,1-3H3/t14-,15-,17+,18+,19-,20-,22-/m0/s1
IUPAC Name
SMILES
[H][C@]12[[email protected]](CCC=C1C=C[[email protected]](C)[C@@H]2CC[C@@H]1C[C@@H](O)CC(=O)O1)OC(=O)[C@@H](C)CC
Taxonomy
ClassificationNot classified
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.
Related Articles
AbsorptionNot Available
Volume of distributionNot Available
Protein bindingNot Available
MetabolismNot Available
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 inhibitorNon-inhibitor0.8909
CYP450 2D6 inhibitorNon-inhibitor0.8903
CYP450 2C19 inhibitorNon-inhibitor0.8513
CYP450 3A4 inhibitorInhibitor0.6571
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
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
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
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 References
  1. Chemspider [Link]
  2. Pubchem [Link]
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

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Nadph binding
Specific Function:
Transmembrane glycoprotein that is the rate-limiting enzyme in cholesterol biosynthesis as well as in the biosynthesis of nonsterol isoprenoids that are essential for normal cell function including ubiquinone and geranylgeranyl proteins.
Gene Name:
HMGCR
Uniprot ID:
P04035
Molecular Weight:
97475.155 Da
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:12433810 ]
  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:12518039 ]
  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:12671581 ]
  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:12677170 ]
  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:12852453 ]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]
  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:10592235 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
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 acyl-CoA ester. Hydrolyzes the methyl ester group of cocaine to form benzoylecgonine. Catalyzes the transesterification of cocaine to form cocaethylene. Displays fatty acid ethyl ester synthase activity,...
Gene Name:
CES1
Uniprot ID:
P23141
Molecular Weight:
62520.62 Da
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:16081098 ]
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Drug created on March 13, 2010 15:07 / Updated on May 07, 2016 21:21