Mevastatin
Explore a selection of our essential drug information below, or:
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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- 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.
Target Actions Organism A3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitorHumans - 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
- Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.
- 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.
Drug Interaction Integrate drug-drug
interactions in your softwareAcenocoumarol The therapeutic efficacy of Acenocoumarol can be increased when used in combination with Mevastatin. Acipimox Acipimox may increase the myopathic rhabdomyolysis activities of Mevastatin. Alendronic acid The risk or severity of myopathy, rhabdomyolysis, and myoglobinuria can be increased when Alendronic acid is combined with Mevastatin. Amiodarone The metabolism of Mevastatin can be increased when combined with Amiodarone. Amphotericin B The 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
- External Links
- 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
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample data
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
- Not Available
- Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) 152 °C PhysProp logP 3.95 SANGSTER (1994) - Predicted Properties
Property Value Source Water Solubility 0.0321 mg/mL ALOGPS logP 4.13 ALOGPS logP 3.62 Chemaxon logS -4.1 ALOGPS pKa (Strongest Acidic) 14.91 Chemaxon pKa (Strongest Basic) -2.8 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 3 Chemaxon Hydrogen Donor Count 1 Chemaxon Polar Surface Area 72.83 Å2 Chemaxon Rotatable Bond Count 7 Chemaxon Refractivity 108.63 m3·mol-1 Chemaxon Polarizability 43.57 Å3 Chemaxon Number of Rings 3 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
Property Value Probability Human Intestinal Absorption + 0.9714 Blood Brain Barrier + 0.639 Caco-2 permeable - 0.6631 P-glycoprotein substrate Substrate 0.7964 P-glycoprotein inhibitor I Non-inhibitor 0.8324 P-glycoprotein inhibitor II Inhibitor 0.6601 Renal organic cation transporter Non-inhibitor 0.8617 CYP450 2C9 substrate Non-substrate 0.8503 CYP450 2D6 substrate Non-substrate 0.9115 CYP450 3A4 substrate Substrate 0.7206 CYP450 1A2 substrate Non-inhibitor 0.8952 CYP450 2C9 inhibitor Non-inhibitor 0.8909 CYP450 2D6 inhibitor Non-inhibitor 0.8903 CYP450 2C19 inhibitor Non-inhibitor 0.8513 CYP450 3A4 inhibitor Inhibitor 0.6571 CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.7992 Ames test Non AMES toxic 0.8927 Carcinogenicity Non-carcinogens 0.9523 Biodegradation Not ready biodegradable 0.8854 Rat acute toxicity 2.6058 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.8359 hERG inhibition (predictor II) Non-inhibitor 0.6699
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 209.0716226 predictedDarkChem Lite v0.1.0 [M-H]- 200.7929226 predictedDarkChem Lite v0.1.0 [M-H]- 203.30531 predictedDeepCCS 1.0 (2019) [M+H]+ 210.2936226 predictedDarkChem Lite v0.1.0 [M+H]+ 201.4421226 predictedDarkChem Lite v0.1.0 [M+H]+ 205.37056 predictedDeepCCS 1.0 (2019) [M+Na]+ 209.4606226 predictedDarkChem Lite v0.1.0 [M+Na]+ 201.1370226 predictedDarkChem Lite v0.1.0 [M+Na]+ 211.28307 predictedDeepCCS 1.0 (2019)
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Catalyzes the conversion of (3S)-hydroxy-3-methylglutaryl-CoA (HMG-CoA) to mevalonic acid, the rate-limiting step in the synthesis of cholesterol and other isoprenoids, thus plays a critical role in cellular cholesterol homeostasis (PubMed:21357570, PubMed:2991281, PubMed:36745799, PubMed:6995544). HMGCR is the main target of statins, a class of cholesterol-lowering drugs (PubMed:11349148, PubMed:18540668, PubMed:36745799).
- Specific Function
- coenzyme A binding
- Gene Name
- HMGCR
- Uniprot ID
- P04035
- Uniprot Name
- 3-hydroxy-3-methylglutaryl-coenzyme A reductase
- Molecular Weight
- 97475.155 Da
References
- 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]
- 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]
- 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]
- 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]
- 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]
- Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
- 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
- Involved in the detoxification of xenobiotics and in the activation of ester and amide prodrugs (PubMed:18762277, PubMed:7980644, PubMed:9169443, PubMed:9490062). Hydrolyzes aromatic and aliphatic esters, but has no catalytic activity toward amides or a fatty acyl-CoA ester (PubMed:18762277, PubMed:7980644, PubMed:9169443, PubMed:9490062). Hydrolyzes the methyl ester group of cocaine to form benzoylecgonine (PubMed:7980644). Catalyzes the transesterification of cocaine to form cocaethylene (PubMed:7980644). Displays fatty acid ethyl ester synthase activity, catalyzing the ethyl esterification of oleic acid to ethyloleate (PubMed:7980644). Converts monoacylglycerides to free fatty acids and glycerol. Hydrolyzes of 2-arachidonoylglycerol and prostaglandins (PubMed:21049984). Hydrolyzes cellular cholesteryl esters to free cholesterols and promotes reverse cholesterol transport (RCT) by facilitating both the initial and final steps in the process (PubMed:11015575, PubMed:16024911, PubMed:16971496, PubMed:18762277). First of all, allows free cholesterol efflux from macrophages to extracellular cholesterol acceptors and secondly, releases free cholesterol from lipoprotein-delivered cholesteryl esters in the liver for bile acid synthesis or direct secretion into the bile (PubMed:16971496, PubMed:18599737, PubMed:18762277).
- Specific Function
- carboxylesterase activity
- Gene Name
- CES1
- Uniprot ID
- P23141
- Uniprot Name
- Liver carboxylesterase 1
- Molecular Weight
- 62520.62 Da
References
- 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