Mevastatin

Identification

Generic Name
Mevastatin
DrugBank Accession Number
DB06693
Background

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.

Type
Small Molecule
Groups
Experimental
Structure
Weight
Average: 390.52
Monoisotopic: 390.240624195
Chemical Formula
C23H34O5
Synonyms
  • Compactin
  • Mevastatin
  • Mevastatina
  • Mévastatine
  • Mevastatinum
External IDs
  • Antibiotic ML 236B
  • CS 500
  • ML 236 B
  • ML-236B

Pharmacology

Indication

Not used therapeutically due to its many side effects.

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Contraindications & Blackbox Warnings
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Pharmacodynamics

The primary cause of cardiovascular disease is atherosclerotic plaque formation. Mevastatin lowers hepatic production of cholesterol to reduce the risk of cardiovascular disease. Mevastatin competitively inhibits HMG-CoA reductase. This inhibition prevents the rate limiting step in cholesterol synthesis. Decreased hepatic cholesterol levels causes increased uptake of low density lipoprotein (LDL) cholesterol and reduces cholesterol levels in the circulation.

Mechanism of action

Mevastatin 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.

TargetActionsOrganism
A3-hydroxy-3-methylglutaryl-coenzyme A reductase
inhibitor
Humans
Absorption

Not Available

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism
Not Available
Route of elimination

Not Available

Half-life

Not Available

Clearance

Not Available

Adverse Effects
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Toxicity

Side 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.

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AcenocoumarolThe therapeutic efficacy of Acenocoumarol can be increased when used in combination with Mevastatin.
AcipimoxAcipimox may increase the myopathic rhabdomyolysis activities of Mevastatin.
Alendronic acidThe risk or severity of myopathy, rhabdomyolysis, and myoglobinuria can be increased when Alendronic acid is combined with Mevastatin.
AmiodaroneThe metabolism of Mevastatin can be increased when combined with Amiodarone.
Amphotericin BThe risk or severity of myopathy, rhabdomyolysis, and myoglobinuria can be increased when Amphotericin B is combined with Mevastatin.
Food Interactions
  • Avoid alcohol.
  • Avoid grapefruit products.

Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as delta valerolactones. These are cyclic organic compounds containing an oxan-2- one moiety.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Lactones
Sub Class
Delta valerolactones
Direct Parent
Delta valerolactones
Alternative Parents
Fatty acid esters / Oxanes / Dicarboxylic acids and derivatives / Secondary alcohols / Carboxylic acid esters / Oxacyclic compounds / Organic oxides / Hydrocarbon derivatives / Carbonyl compounds
Substituents
Alcohol / Aliphatic heteropolycyclic compound / Carbonyl group / Carboxylic acid derivative / Carboxylic acid ester / Delta valerolactone / Delta_valerolactone / Dicarboxylic acid or derivatives / Fatty acid ester / Fatty acyl
Molecular Framework
Aliphatic heteropolycyclic compounds
External Descriptors
carboxylic ester, delta-lactone, carbobicyclic compound, statin (naturally occurring) (CHEBI:34848)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
1UQM1K0W9X
CAS number
73573-88-3
InChI Key
AJLFOPYRIVGYMJ-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
(1S,7S,8S,8aR)-8-{2-[(2R,4R)-4-hydroxy-6-oxooxan-2-yl]ethyl}-7-methyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl (2S)-2-methylbutanoate
SMILES
[H][C@]12[C@H](CCC=C1C=C[C@H](C)[C@@H]2CC[C@@H]1C[C@@H](O)CC(=O)O1)OC(=O)[C@@H](C)CC

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]
KEGG Compound
C13963
PubChem Compound
64715
PubChem Substance
99443247
ChemSpider
58262
BindingDB
50011036
ChEBI
34848
ChEMBL
CHEMBL54440
ZINC
ZINC000003833876
PDBe Ligand
2UO
Wikipedia
Mevastatin
PDB Entries
4oqr
MSDS
Download (350 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount

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)152 °CPhysProp
logP3.95SANGSTER (1994)
Predicted Properties
PropertyValueSource
Water Solubility0.0321 mg/mLALOGPS
logP4.13ALOGPS
logP3.62Chemaxon
logS-4.1ALOGPS
pKa (Strongest Acidic)14.91Chemaxon
pKa (Strongest Basic)-2.8Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count3Chemaxon
Hydrogen Donor Count1Chemaxon
Polar Surface Area72.83 Å2Chemaxon
Rotatable Bond Count7Chemaxon
Refractivity108.63 m3·mol-1Chemaxon
Polarizability43.57 Å3Chemaxon
Number of Rings3Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
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)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSsplash10-03di-2697563470-7ca60296a82091ed4d78
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-000i-0391000000-b79e1e767732f4bf01b7
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-0fe1-3209000000-59aa60ac03d602cd5fad
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-000j-4129000000-c737bab41a01826e51dc
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-052f-1259000000-5fa8f593dff2622b3a25
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-0kbr-1914000000-21af0f4666bfddd9ef60
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-08i3-0894000000-b818b3003f3327e29ae8
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-209.0716226
predicted
DarkChem Lite v0.1.0
[M-H]-200.7929226
predicted
DarkChem Lite v0.1.0
[M-H]-203.30531
predicted
DeepCCS 1.0 (2019)
[M+H]+210.2936226
predicted
DarkChem Lite v0.1.0
[M+H]+201.4421226
predicted
DarkChem Lite v0.1.0
[M+H]+205.37056
predicted
DeepCCS 1.0 (2019)
[M+Na]+209.4606226
predicted
DarkChem Lite v0.1.0
[M+Na]+201.1370226
predicted
DarkChem Lite v0.1.0
[M+Na]+211.28307
predicted
DeepCCS 1.0 (2019)

Targets

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Kind
Protein
Organism
Humans
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...
Gene Name
HMGCR
Uniprot ID
P04035
Uniprot Name
3-hydroxy-3-methylglutaryl-coenzyme A reductase
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. [Article]
  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. [Article]
  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. [Article]
  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. [Article]
  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. [Article]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
  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. [Article]

Enzymes

Kind
Protein
Organism
Humans
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 acy...
Gene Name
CES1
Uniprot ID
P23141
Uniprot Name
Liver carboxylesterase 1
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. [Article]

Drug created at March 13, 2010 22:07 / Updated at February 21, 2021 18:52