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Lovastatin

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Aug 072016
 

Lovastatin3Dan.gifLovastatin.svg

Lovastatin
(+)-Mevinolin
(1S,3R,7S,8S,8aR)-1,2,3,7,8,8a-Hexahydro-3,7-dimethyl-8-[2-[(2R,4R)-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl]ethyl]-1-naphthalenyl (S)-2-Methylbutyrate
(2S)-2-Methylbutanoic acid (1S,3R,7S,8S,8aR)-1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-[(2R,4R)-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl]ethyl]-1-naphthalenyl ester
[1S-[1a(R*),3a,7b,8b(2S*,4S*),8ab]]-2-Methylbutanoic Acid1,2,3,7,8,8a-Hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1-naphthalenyl Ester
1,2,6,7,8,8a-Hexahydro-b,d-dihydroxy-2,6-dimethyl-8-(2-methyl-1-oxobutoxy)-1-naphthaleneheptanoic Acid d-Lactone
2b,6a-Dimethyl-8a-(2-methyl-1-oxobutoxy)mevinic Acid Lactone
6a-Methylcompactin
75330-75-5

Lovastatin (Merck’s Mevacor) is a statin drug, used for lowering cholesterol (hypolipidemic agent) in those withhypercholesterolemia to reduce risk of cardiovascular disease. Lovastatin is a naturally occurring compound found in food such asoyster mushrooms,[2] red yeast rice,[3] and Pu-erh.[4]

Medical uses

The primary uses of lovastatin is for the treatment of dyslipidemia and the prevention of cardiovascular disease.[5] It is recommended to be used only after other measures, such as diet, exercise, and weight reduction, have not improved cholesterol levels.[5]

Pleurotus ostreatus, the oyster mushroom, naturally contains up to 2.8% lovastatin on a dry weight basis.[15]

Structure

 

 

History

 Compactin and lovastatin, natural products with a powerful inhibitory effect on HMG-CoA reductase, were discovered in the 1970s, and taken into clinical development as potential drugs for lowering LDL cholesterol.

However, in 1980, trials with compactin were suspended for undisclosed reasons (rumoured to be related to serious animal toxicity). Because of the close structural similarity between compactin and lovastatin, clinical studies with lovastatin were also suspended, and additional animal safety studies initiated.

In 1982 some small-scale clinical investigations of lovastatin, a polyketide derived natural product isolated from Aspergillus terrus, in very high-risk patients were undertaken, in which dramatic reductions in LDL cholesterol were observed, with very few adverse effects. After the additional animal safety studies with lovastatin revealed no toxicity of the type thought to be associated with compactin, clinical studies resumed.

Large-scale trials confirmed the effectiveness of lovastatin. Observed tolerability continued to be excellent, and lovastatin was approved by the US FDA in 1987.

Lovastatin at its maximal recommended dose of 80 mg daily produced a mean reduction in LDL cholesterol of 40%, a far greater reduction than could be obtained with any of the treatments available at the time. Equally important, the drug produced very few adverse effects, was easy for patients to take, and so was rapidly accepted by prescribers and patients. The only important adverse effect is myopathy/rhabdomyolysis. This is rare and occurs with all HMG-CoA reductase inhibitors.

 Mechanism of action

Lovastatin is an inhibitor of 3-hydroxy-3methylglutaryl-coenzyme A reductase (HMG-CoA reductase), an enzyme which catalyzes the conversion of HMG-CoA to mevalonate. Mevalonate is a required building block for cholesterol biosynthesis and lovastatin interferes with its production by acting as a competitive inhibitor for HMG-CoA which binds to the HMG-CoA reductase. Lovastatin, being inactive in the native form, the form in which it is administered, is hydrolysed to the β-hydroxy acid form in the body and it is this form which is active. Presumably, the reductase acts on the hydrolyzed lovastatin to reduce the carboxylic acid moiety.

Discovery, Biochemistry and Biology

 It is now generally accepted that a major risk factor for the development of coronary heart disease is an elevated concentration of plasma cholesterol, especially lowdensity lipoprotein (LDL) cholesterol. The objective is to decrease excess levels of cholesterol to an amount consistent with maintainence of normal body function. Cholesterol is biosynthesized in a series of more than 25 separate enzymatic reactions that initially involves 3 successive condensations of acetyl-CoA units to form a 6-carbon compound, 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA). This is reduced to mevalonate and then converted in a series of reactions to the isoprenes that are building blocks of squalene, the immediate precursor to sterols, which cyclizes to lanosterol (a methylated sterol) and further metabolized to cholesterol. A number of early attempts to block the synthesis of cholesterol resulted in agents that inhibited late in the biosynthetic pathway between lanosterol and cholesterol. A major rate limiting step in the pathway is at the level of the microsomal enzyme which catalyzes the conversion of HMG CoA to mevalonic acd and which has been considered to be a prime target for pharmacologic intervention for several years.

            HMG CoA reductase occurs early in the biosynthetic pathway and is among the first commited steps to cholesterol formulation. Inhibition of this enzyme could lead to accumulation of HMG CoA, a water-soluble intermediate that is then capable of being readily metabolized that is then capable of being readily metabolized to simpler molecules. This inhibition of reductase would nto lead to accumulation of lipophylic intermediates having a formal sterol ring.

            Lovastatin is the first specific inhibitor of HMG CoA reductase to receive approval for the treatment of hypercholesterolemia. The first breakthrough in efforts to find a potent, specific, competitive inhibitor of HMG CoA reductase occurred in 1976 when Endo et al reported discovery of mevastatin, a highly functionalized fungal metabolite, isolated from cultures of  Penicillium citrium. Mevastatin was demonstrated to be an unusually potent inhibitor of the target enzyme and of cholesterol biosynthesis. Subsequent to the first reports describing mevastatin, efforts were initiated to search for other naturally occurring inhibitors oh HMG CoA reductase. This led to the discovery of a novel fungal metabolite – Lovastatin. The structure of Lovastatin was determined to be different from that of mevastatin by the presence of a 6 alphamethyl group in the hexahydronaphthalene ring.

Key points from the study of the Biosynthesis of Lovastatin :-

– Lovastatin is comprised of 2 polyketide chains derived from acetate that are 8- and 4-

  carbons long coupled in head to tail fashion.

– 6 alphamethyl group and the methyl group on the 4-carbon side chain are derived from

  the methyl group of methionine, and

– 6 alphamethyl group is added before closure of the rings.

This implies that lovastatin is a unique compound synthesized by A. terreus and that mevastatin is not an intermediate in its fornmation.

Cholesterol Biosynthetic Pathway

 

The HMG CoA reductase reaction

 

Biosynthesis — Diels-Alder Catalyzed Cyclization

            In vitro formation of a triketide lactone using a genetically-modified protein derived from 6-deoxyerythronolide B synthase has been demonstrated. The stereochemistry of the molecule supports the intriguing idea that an enzyme-catalyzed Diels-Alder reaction may occur during assembly of the polyketide chain. It thus appears that biological Diels-Alder reactions may be triggered by generation of reactive triene systems on an enzyme surface.

 

Biosynthesis – Using Broadly specific Acyltransferase

It has been found that a dedicated acyltransferase, LovD, is encoded in the lovastatin biosynthetic pathway. LovD has a broad substrate specificity towards the acyl carrier, the acyl substrate and the decalin acyl acceptor. It efficiently catalyzes the acyl transfer from coenzyme A thoesters or N-acetylcysteamine (SNAC) thioesters to monacolin J.

            The biosynthesis of Lovastatin is coordinated by two iterative type I polyketide synthases and numerous accessory enzymes. Nonketide, the intermediate biosynthetic precursor of Lovastatin, is assembeled by the upstream megasynthase LovB (also known as lovastatin nonaketide synthase), enoylreductase LovC, and CYP450 oxygenases. The five carbon unit side chain is synthesized by LovF (also known as lovastatin diketide synthase) through a single condensation diketide undergoes methylation and reductive tailoring by the individual LovF catalytic domains to yield an α-S-methylbutyryl thioester covalently attached to the phosphopantetheine arm on the acyl carrier protein (ACP) domain of LovF. Encoded in the gene cluster is a 46kDa protein, LovD, which was initially identified as an esterase homolog. LovD, which was initially identified as an esterase homolog. LovD was suggested to catalyze the last step of lovastatin biosynthesis that regioselectively transacylates the acyl group from LovF to the C8 hydroxyl group of the Nonaketide to yield Lovastatin. 

 

  

K. Auclair, A. Sutherland, J. Kennedy, D. J. Witter, J. P. Van den Heever, C. R. Hutchinson and J. C. Vederas, Lovastatin Nonaketide Synthase Catalyses An Intramolecular Diels-Alder Reaction Of A Substrate Analogue, J. Am. Chem. Soc., 2000, 122, 11519-11520. DOI: 10.1021/ja003216+

 

JACS(Lov2)

http://pubs.rsc.org/en/content/articlelanding/2013/np/c2np20069d/unauth#!divAbstract

 

196264.fig.002

http://www.hindawi.com/journals/bmri/2012/196264/#B30

  1. Z. Jia, X. Zhang, Y. Zhao, and X. Cao, “Enhancement of lovastatin production by supplementing polyketide antibiotics to the submerged culture of Aspergillus terreus,” Applied Biochemistry and Biotechnology, vol. 160, no. 7, pp. 2014–2025, 2010. 

Patent

https://www.google.com/patents/US6307066

PATENT

https://www.google.com/patents/WO2002009697A1?cl=en

https://www.google.com/patents/EP0625208B1?cl=en

Total Synthesis

A major bulk of work in the synthesis of Lovastatin was done by M. Hirama in the 1980’s. Hirama synthesized Compactin and used one of the intermediates to follow a different path to get to Lovastatin. The synthetic sequence is shown in the schemes below. The γ-lactone was synthesized using Yamada methodology starting with aspartic acid. Lactone opening was done using lithium methoxide in methanol and then silylation to give a separable mixture of the starting lactone and the silyl ether. The silyl ether on hydrogenolysis followed by Collins oxidation gave the aldehyde. Stereoselective preparation of (E,E)-diene was accomplished by addition of trans-crotyl phenyl sulfone anion, followed by quenching with Ac2O and subsequent reductive elimination of sulfone acetate. Condensation of this with Lithium anion of dimethyl methylphosphonate gave compound 1.Compound 2 was synthesized as shown in the scheme in the synthetic procedure. Compounds 1 and 2 were then combined together using 1.3eq sodium hydride in THF followed by reflux in chlorobenzene for 82 hrs under nitrogen to get the enone 3.

Simple organic reactions were used to get to Lovastatin as shown in the scheme.

 

 

 

 

Pharmacopoeia Information

Lovastatin tablets are preserved in well closed, light resistant containers. Protected from light and stored either in a cool place or at controlled room temperature.

Lovastatin tablets are tested for Dissolution and Assay as per the USP.

Limit for Dissolution – Not less than 80% (Q) of the labeled amount of Lovastatin is dissolved in 30 mins.

Limit for Assay – Each tablet contains not less than 90% and not more than 110% of the labeled amount of Lovastatin, tested by HPLC analysis.

Lovastatin raw material contains 5 impurities – A, B, C, D and E (as shown below).

 

 

Market brands and other analogues  

There are other derivatives of Lovastatin which possess cholesterol reducing activity. Simvastatin (Zocor®) is another statin closely related to Lovastatin, differing only by the presence of a methyl group in the butanoyl ester moiety. Both effective in lowering total cholesterol.

Another statin having vastly different structure but a popular drug – Atorvastatin (Lipitor®), administered as a calcium salt is a pyrrole derivative and a synthetic compound rather than a natural product.

NMR

  1 H NMR spectrum of lovastatin, 300 MHz, solvent CDCl 3 . 

STR1 str2 STR3

STR1 str2 STR3UV LOVASTATIN

Figure 6. The mean FT-IR spectra (the calibration set) and variables selected after application of UVE-PLS for modelling lovastatin (triangles) and wavenumbers for characteristic peaks for lovastatin IR spectrum (dots).

PATENT

https://www.google.com/patents/EP0702679B1?cl=en

Lovastatin is produced as a secondary metabolite of the fungusAspergillus terreus (US 4,231,938) deposited in American Type Culture Collection under Nos. ATCC 20541, ATCC 20542, and Monascus ruberdeposited in Fermentation Research Institute Agency of Industrial Science and Technology, Ministry of International Trade and Industry, Japan (DE 30 06 216 A1) under No. Ferm 4822. Other kinds of microorganisms producing lovastatin are known as well, e.g. a mutant of the microorganism Aspergillus terreus andAspergillus oryzae marked ATCC 74135.

Lovastatin is chemically 1′,2′,6′,7′,8a’-hexahydro-3,5-dihydroxy-2′,6′-dimethyl-8′-2″-methyl-1″-oxobutoxy)-1-naphtalene heptanoic acid-5-lactone (Stubbs et al., 1986) of the formula (EP 0 033 537 A1)

Figure 00010001

An active form of lovastatin is also an acid, which is chemically 1,2,6,8,8a-hexahydro-β,δ-dihydroxy-1-naphtalene heptanoic acid (Alberts et al., 1980) of the formula (EP 0 022 478 A1)

Figure 00020001

The lactone form of lovastatin is used as an agent for reducing cholesterol level in blood (Scott M.G. and Vega G.L, 1985). It inhibits the biosynthesis of mevalonic acid by inhibition of 3-hydroxy-3-methylglutaryl A reductase coenzyme (HMG-CoA reductase, E.C. 1.1.1.34) (Zubay et al., 1984).

Prior Art

After the completed fermentation, lovastatin is present in the broth in the lactone form (compound I) and in the acid form (compound II). In the isolation process as disclosed in EP 0 033 536 A2, lovastatin is extracted from the broth with ethyl acetate. The extract is concentrated by vacuum distillation. Since lovastatin is present in the lactone form as well as in the acid form and only the lactone is of commercial interest, the acid form should be converted into the lactone. The lactonisation is carried out by the reflux of the concentrate in toluene at 106 °C for 2 hours. After the lactonisation is complete, the solution is concentrated to a small volume. A pure substance is obtained by means of purifying the concentrate on columns packed with silica gel, in the presence of solvents such as ethyl acetate or n-hexane. The collected fractions are again concentrated in vacuo and then pure lovastatin crystallizes in the lactone form.

Due to the sophisticated multi-step procedure and vigorous conditions applied during the isolation, the yields of lovastatin are generally low. Different solvents, which in part exhibit toxicity, are used such as benzene, toluene, acetonitrile or ethyl acetate. Hence working with these solvents endangers the health of the persons involved and poses a problem with respect to the environment.

 

 

 

 

 

 

 

 

https://www.google.com/patents/EP0702679B1?cl=en

The structure was confirmed by IR spectroscopy (Fig.1), mass spectroscopy (Fig. 2), NMR (Fig. 3) and UV spectroscopy (Fig. 4).

STR1 str2

 

IR spectrum of lovastatin.IR spectrum of lovastatin.

 

 Lovastatin

Title: Lovastatin
CAS Registry Number: 75330-75-5
CAS Name: (2S)-2-Methylbutanoic acid (1S,3R,7S,8S,8aR)-1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-[(2R,4R)-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl]ethyl]-1-naphthalenyl ester
Additional Names: (1S,3R,7S,8S,8aR)-1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-[(2R,4R)-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl]ethyl]-1-naphthalenyl (S)-2-methylbutyrate; 1,2,6,7,8,8a-hexahydro-b,d-dihydroxy-2,6-dimethyl-8-(2-methyl-1-oxobutoxy)-1-naphthaleneheptanoic acid d-lactone; 2b,6a-dimethyl-8a-(2-methyl-1-oxobutoxy)mevinic acid lactone; mevinolin; 6a-methylcompactin; monacolin K
Manufacturers’ Codes: MK-803
Trademarks: Lovalip (Merck & Co.); Mevacor (Merck & Co.); Mevinacor (Merck & Co.); Mevlor (Merck & Co.); Sivlor (Sidus)
Molecular Formula: C24H36O5
Molecular Weight: 404.54
Percent Composition: C 71.26%, H 8.97%, O 19.77%
Literature References: Fungal metabolite; potent inhibitor of HMG-CoA reductase, the rate controlling enzyme in cholesterol biosynthesis. Isoln from Monascus ruber: A. Endo, J. Antibiot. 32, 852 (1979); from Aspergillus terreus: R. L. Monaghan et al., US4231938 (1980 to Merck & Co.). Structure and biochemical properties: A. W. Alberts et al., Proc. Natl. Acad. Sci. USA 77, 3957 (1980). Total synthesis: M. Hirama, M. Iwashita, Tetrahedron Lett. 24, 1811 (1983). Review of syntheses: T. Rosen, C. H. Heathcock, Tetrahedron 42, 4909-4951 (1986). Biosynthesis: M. D. Greenspan, J. B. Yudkovitz, J. Bacteriol. 162, 704 (1985); R. N. Moore et al., J. Am. Chem. Soc. 107, 3694 (1985). HPLC determn in plasma and bile: R. J. Stubbs et al., J. Chromatogr. 383,438 (1986). Clinical pharmacology: S. M. Grundy, G. L. Vega, J. Lipid Res. 26, 1464 (1985). Clinical comparison with gemfibrozil,q.v.: M. J. Tikkanen et al., Am. J. Cardiol. 62, 35J (1988). Review of clinical experience: J. A. Tobert, Am. J. Cardiol. 62, 28J-34J (1988). Comprehensive description: G. S. Brenner et al., Anal. Profiles Drug Subs. Excip. 21, 277-305 (1992). Prevention of acute coronary events in men and women with average cholesterol levels: J. R. Downs et al., J. Am. Med. Ass

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Lovastatin
Lovastatin.svg
Lovastatin3Dan.gif
Systematic (IUPAC) name
(1S,3R,7S,8S,8aR)-8-{2-[(2R,4R)-4-Hydroxy-6-oxooxan-2-yl]ethyl}-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl (2S)-2-methylbutanoate
Clinical data
Trade names Mevacor
AHFS/Drugs.com Monograph
MedlinePlus a688006
Pregnancy
category
  • US: X (Contraindicated)
Routes of
administration		 Oral
Legal status
Legal status
Pharmacokinetic data
Bioavailability <5%[1]
Protein binding >98%[1]
Metabolism Hepatic (CYP3A andCYP2C8 substrate)[1]
Biological half-life 2–5 hours[1]
Excretion Faeces (83%), urine (10%)[1]
Identifiers
CAS Number 75330-75-5 Yes
ATC code C10AA02 (WHO)
PubChem CID 53232
IUPHAR/BPS 2739
DrugBank DB00227 Yes
ChemSpider 48085 Yes
UNII 9LHU78OQFD Yes
KEGG D00359 Yes
ChEBI CHEBI:40303 Yes
ChEMBL CHEMBL503 Yes
Synonyms Monacolin K, Mevinolin
Chemical data
Formula C24H36O5
Molar mass 404.54 g/mol

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