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 category	US: X (Contraindicated)
Legal status	US: ℞-only
Routes of administration	Oral
Pharmacokinetic data
Bioavailability	<5%
Protein binding	>98%
Metabolism	Hepatic (CYP3A and CYP2C8 substrate)
Biological half-life	2-5 hours
Excretion	Faeces (83%), urine (10%)
Identifiers
CAS Number	75330-75-5 Y
ATC code	C10AA02 (WHO)
PubChem	CID: 53232
IUPHAR/BPS	2739
DrugBank	DB00227 Y
ChemSpider	48085 Y
UNII	9LHU78OQFD Y
KEGG	D00359 Y
ChEBI	CHEBI:40303 Y
ChEMBL	CHEMBL503 Y
Chemical data
Formula	C24H36O5
Molecular mass	404.54 g/mol
SMILES O=C(O[C@@H]1[C@H]3C(=C/[C@H](C)C1)\C=C/[C@@H]([C@@H]3CC[C@H]2OC(=O)C[C@H](O)C2)C)[C@@H](C)CC
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
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Lovastatin (Merck's Mevacor) is a statin drug, used for lowering cholesterol (hypolipidemic agent) in those with hypercholesterolemia to reduce risk of cardiovascular disease. Lovastatin is a naturally occurring compound found in food such as oyster mushrooms, red yeast rice, and Pu-erh.

Medical uses

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

Side effects

Lovastatin is usually well tolerated, with the most common side effects being, in approximately descending order of frequency: creatine phosphokinase elevation, flatulence, abdominal pain, constipation, diarrhoea, muscle aches or pains, nausea, indigestion, weakness, blurred vision, rash, dizziness and muscle cramps. As with all statin drugs, it can rarely cause myopathy, hepatotoxicity (liver damage), dermatomyositis 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. Other uncommon side effects that should be promptly mentioned to either the prescribing doctor or an emergency medical service include:

2

These less serious side effects should still be reported if they persist or increase in severity:

2

Contraindications

Contraindications, conditions that warrant withholding treatment with lovastatin, include pregnancy, breast feeding, and liver disease. Lovastatin is contraindicated during pregnancy (Pregnancy Category X); it may cause birth defects such as skeletal deformities or learning disabilities. Due to its potential to disrupt infant lipid metabolism, lovastatin should not be taken while breastfeeding. Patients with liver disease should not take lovastatin.

Interactions

As with atorvastatin, simvastatin, and other statin drugs metabolized via CYP3A4, drinking grapefruit juice during lovastatin therapy may increase the risk of side effects. Components of grapefruit juice, the flavonoid naringin, or the furanocoumarin bergamottin inhibit CYP3A4 in vitro, and may account for the in vivo effect of grapefruit juice concentrate decreasing the metabolic clearance of lovastatin, and increasing its plasma concentrations.

Mechanism of action

Lovastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase), an enzyme that 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 reversible competitive inhibitor for HMG-CoA, which binds to the HMG-CoA reductase. Lovastatin is a prodrug, an inactive lactone in its native form, the gamma-lactone closed ring form in which it is administered, is hydrolysed in vivo to the β-hydroxy acid open ring form; which is the active form.

Lovastatin and other statins have recently been studied for their chemopreventive and chemotherapeutic effects in certain cancers. However, based on clinical evidence, such effects could not be demonstrated. 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.

History

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

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.

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. It was the first statin approved by the FDA.

Lovastatin is also naturally produced by certain higher fungi, such as Pleurotus ostreatus (oyster mushroom) and closely related Pleurotus spp. Research into the effect of oyster mushroom and its extracts on the cholesterol levels of laboratory animals has been extensive, although the effect has been demonstrated in a very limited number of human subjects.

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. Judge Dale A. Kimball of Federal District Court, granted a motion by Cholestin's manufacturer, Pharmanex, that the agency's ban was illegal under the 1994 Dietary Supplement Health and Education Act because the product was marketed as a dietary supplement, not a drug.

Discovery, biochemistry and biology

A ball-and-stick model of lovastatin

An elevated concentration of plasma cholesterol, especially low-density lipoprotein (LDL) cholesterol, is now generally accepted as a major risk factor for the development of coronary heart disease. 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 three successive condensations of acetyl-CoA units to form the six-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.

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 was 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 the 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 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, two and four carbons long, coupled in head-to-tail fashion.
• The six alphamethyl group and the methyl group on the four-carbon side-chain are derived from the methyl group of methionine.
• The 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 formation.

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, "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 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. 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 glutamic 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 1.3 eq sodium hydride in THF followed by reflux in chlorobenzene for 82 hr 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

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

Other applications

In plant physiology, lovastatin has occasionally been used as inhibitor of cytokinin biosynthesis.

See also

• Medicinal molds