Lovastatin

Lovastatin

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 cat.	X(US)
Legal status	℞-only (US)
Routes	oral
Pharmacokinetic data
Bioavailability	<5%
Protein binding	>95%
Metabolism	hepatic (CYP3A substrate)
Half-life	1.1-1.7 hours
Excretion	negligible
Identifiers
CAS number	75330-75-5 Y
ATC code	C10AA02
PubChem	CID 53232
DrugBank	APRD00370
ChemSpider	48085 Y
UNII	9LHU78OQFD Y
KEGG	D00359 Y
ChEBI	CHEBI:40303 Y
ChEMBL	CHEMBL503 Y
Chemical data
Formula	C24H36O5
Mol. mass	404.54 g/mol
SMILES	eMolecules & PubChem
InChI InChI=1S/C24H36O5/c1-5-15(3)24(27)29-21-11-14(2)10-17-7-6-16(4)20(23(17)21)9-8-19-12-18(25)13-22(26)28-19/h6-7,10,14-16,18-21,23,25H,5,8-9,11-13H2,1-4H3/t14-,15-,16-,18+,19+,20-,21-,23-/m0/s1 Y Key:PCZOHLXUXFIOCF-BXMDZJJMSA-N Y
N(what is this?)  (verify)

Lovastatin is a member of the drug class of statins, used for lowering cholesterol (hypolipidemic agent) in those with hypercholesterolemia and so preventing cardiovascular disease. Lovastatin is a naturally occurring drug found in food such as oyster mushrooms^[1] and red yeast rice.^[2]

Medical uses

The primary uses of lovastatin is for the treatment of dyslipidemia and the prevention of cardiovascular disease.^[3] It is recommended to be used only after other measures such as diet, exercise, and weight reduction have not improved cholesterol levels.^[3]

History

The "oyster mushroom", a culinary mushroom, naturally contains up to 2.8% lovastatin on a dry weight basis. ^[4]

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.^[5][6]

In 1982, some small-scale clinical investigations of lovastatin, a polyketide-derived natural product isolated from Aspergillus terreus, 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 continued.

Large-scale trials confirmed the effectiveness of lovastatin. Observed tolerability continued to be excellent, and lovastatin was approved by the US FDA in 1987.^[7] It was the first statin approved by the FDA.^[8]

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 most significant adverse effect is rhabdomyolysis; this is rare and may occur with the use of any HMG-CoA reductase inhibitor.

Lovastatin is also naturally produced by certain higher fungi such as Pleurotus ostreatus (oyster mushroom) and closely related Pleurotus spp.^[9] There has been extensive research into the effect of oyster mushroom and its extracts on the cholesterol levels of laboratory animals,^{[10][11][9][12][13][14][15][16][17][18][19][20]} although the effect has been demonstrated in a very limited number of human subjects.^[21]

In 1998, the FDA placed a ban on the sale of dietary supplements derived from red yeast rice, which naturally contains lovastatin, arguing that products containing prescription agents require drug approval.^{[citation needed]} This ban was subsequently rescinded, in light of law that upholds that natural products are not patentable.

Mechanism of action

Lovastatin is an inhibitor of 3-hydroxy-3methylglutaryl-coenzyme A reductase (HMG-CoA reductase), an enzyme that catalyzes the conversion of HMG-CoA to mevalonate.^[22] Mevalonate is a required building block for cholesterol biosynthesis and lovastatin interferes with its production by acting as a reversible 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; it is this form that is active.

Discovery, biochemistry and biology

A ball-and-stick model of Lovastatin

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 low-density lipoprotein (LDL) cholesterol.^[23] The objective is to decrease excess levels of cholesterol to an amount consistent with maintenance 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 the 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 that catalyzes the conversion of HMG CoA to mevalonic acid and that has been considered to be a prime target for pharmacologic intervention for several years.^[22]

HMG CoA reductase occurs early in the biosynthetic pathway and is among the first committed 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 to simpler molecules. This inhibition of reductase would lead to accumulation of lipophylic intermediates with 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.^[24] 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 of 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 six alphamethyl group in the hexahydronaphthalene ring.

Key points from the study of the biosynthesis of lovastatin :-

• Lovastatin is composed of two polyketide chains derived from acetate that are two and four carbons long coupled in head to tail fashion.
• six alphamethyl group and the methyl group on the four-carbon side-chain are derived from the methyl group of methionine
• six 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

HMG CoA reductase reaction

Biosynthesis using 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. Witter and Vederas observed that "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."^[25]

Biosynthesis using Diels-Alder catalyzed cyclization

Biosynthesis using broadly specific acyltransferase

Total synthesis

A major bulk of work in the synthesis of lovastatin was done by M. Hirama in the 1980s.^{[26] [27]} 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.

Synthesis of compounds 1 and 2

Complete lovastatin synthesis

Pharmacology and dose

Main article: statin

The mode of action of statins is HMG-CoA reductase enzyme inhibition. This enzyme is needed by the body to make cholesterol.

Lovastatin causes cholesterol to be lost from LDL, but also reduces the concentration of circulating LDL (low-density lipoprotein) particles. Apolipoprotein B concentration falls substantially during treatment with lovastatin. Lovastatin's ability to lower LDL is thought to be due to a reduction in VLDL, which is a precursor to LDL. Also, Lovastatin may increase the number of LDL receptors on the surface of cell membranes, and thus increase the breakdown of LDL.

Lovastatin can also produce slight to moderate increases in HDL, and slight to moderate decreases in triglycerides. Both of these effects are typically beneficial to a patient with a poor lipid profile.

Both lovastatin and its b-hydroxyacid metabolite are highly bound (>95%) to human plasma proteins. Animal studies demonstrated that lovastatin crosses the blood-brain and placental barriers.^[28] Elderly patients, or those with renal insufficiency, may have higher plasma concentrations of lovastatin after administration and may require a lower dose. The usual recommended starting dose is 20 mg once a day given with the evening meal, and the dose range is 10–80 mg a day in a single dose, or divided into two doses.

Lovastatin and other statins have recently been studied for their chemopreventive and chemotherapeutic effects in certain cancers. However, based on clinical evidence such effect could not be demonstrated.^[29] In principle, independent of their hydroxymethyl glutaryl (HMG)-CoA reductase inhibition, lovastatin and other statins reduce proteasome activity, leading to an accumulation of cyclin-dependent kinase inhibitors p21 and p27, and G1 phase arrest in breast cancer cell lines. For that purpose, lovastatin is also used experimentally.^[30]

Side effects

Lovastatin is usually well tolerated. Lovastatin, and all statin drugs, can rarely cause myopathy or rhabdomyolysis. This can be life-threatening if not recognised and treated in time, so any unexplained muscle pain or weakness whilst on lovastatin should be promptly mentioned to the prescribing doctor.

Lovastatin is contraindicated during pregnancy (Pregnancy Category X); it may cause skeletal deformities or learning disabilities.

Drug interactions

As with atorvastatin, simvastatin and other statin drugs metabolized via CYP3A4, drinking grapefruit juice during lovastatin therapy increases the risk of serious side-effects. Grapefruit juice inhibits CYP3A4, thereby decreasing lovastatin's metabolism and increasing its plasma concentrations.

Lovastatin at doses higher than 20 mg per day should not be used in conjunction with gemfibrozil or other fibrates, niacin, or ciclosporin. This is because of the significantly increased risk of rhabdomyolysis.

Pharmacopoeia information

Lovastatin tablets are preserved when stored in well-closed, light-resistant containers 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 minutes.

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.

Brand names

• Mevacor
• Advicor (as a combination with niacin)
• Altocor
• Altoprev
• Statosan (Atos Pharma)

Other applications

In plant physiology, lovastatin has occasionally been used as inhibitor of cytokinin biosynthesis.^[31]

Lovastatin is currently in phase one of clinical trial (NCT00352599) to evaluate safety for treatment of cognitive deficits in patients with Neurofibromatosis type I. This drug has been shown to reverse spatial deficits in mice.^[32]

References

1. ^ . Lovastatin also goes by the trade-name of Mevacor(Merck & Co.) in the United States Gunde-Cimerman N, Cimerman A. (Mar 1995). "Pleurotus fruiting bodies contain the inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase-lovastatin.". Exp Mycol. 19 (1): 1–6. doi:10.1006/emyc.1995.1001. PMID 7614366. 
2. ^ Liu J, Zhang J, Shi Y, Grimsgaard S, Alraek T, Fønnebø V (2006). "Chinese red yeast rice (Monascus purpureus) for primary hyperlipidemia: a meta-analysis of randomized controlled trials". Chin Med 1: 4. doi:10.1186/1749-8546-1-4. PMC 1761143. PMID 17302963. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1761143. 
3. ^ ^{a b} "Lovastatin". The American Society of Health-System Pharmacists. http://www.drugs.com/monograph/Lovastatin.html. Retrieved 3 April 2011. 
4. ^ Alarcón J, Aguila S, Arancibia-Avila P, Fuentes O, Zamorano-Ponce E, Hernández M (2003 Jan-Feb). "Production and purification of statins from Pleurotus ostreatus (Basidiomycetes) strains". Z Naturforsch C 58 (1-2): 62–4. PMID 12622228. 
5. ^ Vederas JC, Moore RN, Bigam G, Chan KJ (1985). "Biosynthesis of the hypocholesterolemic agent mevinolin by Aspergillus terreus. Determination of the origin of carbon, hydrogen and oxygen by 13C NMR and mass spectrometry". J Am Chem Soc 107: 3694–701. doi:10.1021/ja00298a046. 
6. ^ Alberts AW, Chen J, Kuron G, Hunt V, Huff J, Hoffman C, Rothrock J, Lopez M, Joshua H, Harris E, Patchett A, Monaghan R, Currie S, Stapley E, Albers-Schonberg G, Hensens O, Hirshfield J, Hoogsteen K, Liesch J, Springer J (July 1980). "Mevinolin: a highly potent competitive inhibitor of hydroxymethlglutaryl-coenzyme A reductase and a cholesterol-lowering agent". Proc Natl Acad Sci U S A 77 (7): 3957–61. doi:10.1073/pnas.77.7.3957. PMC 349746. PMID 6933445. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=349746. 
7. ^ FDA Orange Book Detail for application N019643 showing approval for 20 mg tablets on Aug 31, 1987 and 40 mg tablets on Dec 14, 1988
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10. ^ Hossain S, Hashimoto M, Choudhury EK, et al. (July 2003). "Dietary mushroom (Pleurotus ostreatus) ameliorates atherogenic lipid in hypercholesterolaemic rats". Clin Exp Pharmacol Physiol 30 (7): 470–5. doi:10.1046/j.1440-1681.2003.03857.x. PMID 12823261. 
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15. ^ Bobek P, Ozdín L, Kuniak L (August 1996). "Effect of oyster mushroom (Pleurotus Ostreatus) and its ethanolic extract in diet on absorption and turnover of cholesterol in hypercholesterolemic rat". Nahrung 40 (4): 222–4. doi:10.1002/food.19960400413. PMID 8810086. 
16. ^ Bobek P, Ozdín O, Mikus M (1995). "Dietary oyster mushroom (Pleurotus ostreatus) accelerates plasma cholesterol turnover in hypercholesterolaemic rat". Physiol Res 44 (5): 287–91. PMID 8869262. 
17. ^ Bobek P, Ozdin L, Kuniak L (1995). "The effect of oyster mushroom (Pleurotus ostreatus), its ethanolic extract and extraction residues on cholesterol levels in serum, lipoproteins and liver of rat". Nahrung 39 (1): 98–9. doi:10.1002/food.19950390113. PMID 7898579. 
18. ^ Bobek P, Ozdin L, Kuniak L (March 1994). "Mechanism of hypocholesterolemic effect of oyster mushroom (Pleurotus ostreatus) in rats: reduction of cholesterol absorption and increase of plasma cholesterol removal". Z Ernahrungswiss 33 (1): 44–50. doi:10.1007/BF01610577. PMID 8197787. 
19. ^ Chorváthová V, Bobek P, Ginter E, Klvanová J (1993). "Effect of the oyster fungus on glycaemia and cholesterolaemia in rats with insulin-dependent diabetes". Physiol Res 42 (3): 175–9. PMID 8218150. 
20. ^ Bobek P, Ginter E, Jurcovicová M, Kuniak L (1991). "Cholesterol-lowering effect of the mushroom Pleurotus ostreatus in hereditary hypercholesterolemic rats". Ann. Nutr. Metab. 35 (4): 191–5. doi:10.1159/000177644. PMID 1897899. 
21. ^ Khatun K, Mahtab H, Khanam PA, Sayeed MA, Khan KA (January 2007). "Oyster mushroom reduced blood glucose and cholesterol in diabetic subjects". Mymensingh Med J 16 (1): 94–9. PMID 17344789. 
22. ^ ^{a b} Alberts AW (1998). "Discovery, biochemistry and biology of lovastatin". The American Journal of Cardiology 62 (15): 10J–15J. doi:10.1016/0002-9149(88)90002-1. PMID 3055919. 
23. ^ Coronary heart disease: MedLine Plus Medical Encyclopedia
24. ^ Endo, Akira; Kuroda M., Tsujita Y. (December 1976). "ML-236A, ML-236B, and ML-236C, new inhibitors of cholesterogenesis produced by Penicillium citrinium". Journal of Antibiotics (Tokyo) 29 (12): 1346–8. PMID 1010803. 
25. ^ Witter DJ, Vederas JC (1996). "Putative Diels-Alder catalyzed cyclization during the biosynthesis of lovastatin". J Org Chem 61 (8): 2613–23. doi:10.1021/jo952117p. PMID 11667090. 
26. ^ Hirama M, Vet M (1982). "A chiral total synthesis of compactin". J. Am. Chem. Soc. 104: 4251. doi:10.1021/ja00379a037. 
27. ^ Hirama M, Iwashita (1983). "Synthesis of (+)-Mevinolin starting from Naturally occurring building blocks and using an asymmetry inducing reaction". Tetrahedron Lett. 24: 1811–1812. doi:10.1016/S0040-4039(00)81777-3. 
28. ^ "Lovastatin". Rxlist.com. http://www.rxlist.com/cgi/generic/lovastat.htm. 
29. ^ Katz, MS (2005). "Therapy insight: Potential of statins for cancer chemoprevention and therapy.". Nature clinical practice. Oncology 2 (2): 82–9. doi:10.1038/ncponc0097. PMID 16264880. http://www.ncbi.nlm.nih.gov/pubmed/16264880. 
30. ^ Rao S, Porter DC, Chen X, Herliczek T, Lowe M, Keyomarsi K (July 1999). "Lovastatin-mediated G1 arrest is through inhibition of the proteasome, independent of hydroxymethyl glutaryl-CoA reductase". Proc. Natl. Acad. Sci. U.S.A. 96 (14): 7797–802. doi:10.1073/pnas.96.14.7797. PMC 22141. PMID 10393901. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=22141. 
31. ^ Hartig K, Beck E (2005). "Assessment of lovastatin application as tool in probing cytokinin-mediated cell cycle regulation". Physiologia Plantarum 125 (2): 260–267. doi:10.1111/j.1399-3054.2005.00556.x. 
32. ^ "Trial to Evaluate the Safety of Lovastatin in Individuals With Neurofibromatosis Type I (NF1)"