Lovastatin: Difference between revisions
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--><ref>{{cite journal | author = Hirama M, Iwashita | title = Synthesis of (+)-Mevinolin starting from Naturally occurring building blocks and using an asymmetry inducing reaction | journal = Tetrahedron Lett.| pages = 1811–1812| year = 1983 | doi = 10.1016/S0040-4039(00)81777-3| volume = 24}}</ref> |
--><ref>{{cite journal | author = Hirama M, Iwashita | title = Synthesis of (+)-Mevinolin starting from Naturally occurring building blocks and using an asymmetry inducing reaction | journal = Tetrahedron Lett.| pages = 1811–1812| year = 1983 | doi = 10.1016/S0040-4039(00)81777-3| volume = 24}}</ref> |
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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 |
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 [[Acetic anhydride|Ac<sub>2</sub>O]] 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. |
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Simple organic reactions were used to get to lovastatin as shown in the scheme. |
Simple organic reactions were used to get to lovastatin as shown in the scheme. |
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Revision as of 21:29, 24 January 2011
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| Clinical data | |
|---|---|
| Routes of administration | oral |
| ATC code | |
| Legal status | |
| Legal status |
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| Pharmacokinetic data | |
| Bioavailability | <5% |
| Protein binding | >95% |
| Metabolism | hepatic (CYP3A substrate) |
| Elimination half-life | 1.1-1.7 hours |
| Excretion | negligible |
| Identifiers | |
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| CAS Number | |
| PubChem CID | |
| DrugBank | |
| ChemSpider | |
| UNII | |
| KEGG | |
| ChEMBL | |
| CompTox Dashboard (EPA) | |
| ECHA InfoCard | 100.115.931 |
| Chemical and physical data | |
| Formula | C24H36O5 |
| Molar mass | 404.54 g/mol g·mol−1 |
| 3D model (JSmol) | |
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| (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]
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.[4][5]
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.[6] It was the first statin approved by the FDA.[7]
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[citation needed] important adverse effect is myopathy/rhabdomyolysis. This is rare and occurs with all HMG-CoA reductase inhibitors.
Lovastatin is also naturally produced by certain higher fungi such as Pleurotus ostreatus (oyster mushroom) and closely related Pleurotus spp.[8] There has been extensive research into the effect of oyster mushroom and its extracts on the cholesterol levels of laboratory animals,[9][10][8][11][12][13][14][15][16][17][18][19] although the effect has been demonstrated in a very limited number of human subjects.[20]
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 natural products are not patentable.
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.[21] 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 and it is this form which is active.
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 low density lipoprotein (LDL) cholesterol.[22] 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 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 acid and which has been considered to be a prime target for pharmacologic intervention for several years.[21]
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 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.[23] 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, and
- 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.
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."[24]
Total synthesis
A major bulk of work in the synthesis of lovastatin was done by M. Hirama in the 1980s.[25] [26] 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.
Pharmacology and dose
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.[27] 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.
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 all the statin drugs, drinking grapefruit juice during therapy increases the risk of serious side effects. Grapefruit juice inhibits CYP3A4, and thus decreases the metabolism of statins, increasing their 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 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).
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.[28]
See also
References
- ^ . Lovastatin also goes by the trade-name of Mevacor(Merck & Co.) in the United States
Gunde-Cimerman N, Cimerman A. (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.
{{cite journal}}: Unknown parameter|month=ignored (help) - ^ 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.
{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link) - ^ 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 pages=62–4): 62–4. PMID 12622228.
{{cite journal}}: Check date values in:|date=(help); Missing pipe in:|issue=(help)CS1 maint: multiple names: authors list (link) - ^ 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.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ 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.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=019643&TABLE1=OB_Rx 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
- ^ Endo, Akira (2004). "The origin of the statins". Atheroscler Suppl. 5 (3): 125–30. doi:10.1016/j.atherosclerosissup.2004.08.033. PMID 15531285.
{{cite journal}}: Unknown parameter|month=ignored (help) - ^ a b Bobek P, Ozdín L, Galbavý S (1998). "Dose- and time-dependent hypocholesterolemic effect of oyster mushroom (Pleurotus ostreatus) in rats". Nutrition. 14 (3): 282–6. doi:10.1016/S0899-9007(97)00471-1. PMID 9583372.
{{cite journal}}: CS1 maint: multiple names: authors list (link) Cite error: The named reference "pmid9583372" was defined multiple times with different content (see the help page). - ^ Hossain S, Hashimoto M, Choudhury EK; et al. (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.
{{cite journal}}: Explicit use of et al. in:|author=(help); Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Bobek P, Galbavý S (1999). "Hypocholesterolemic and antiatherogenic effect of oyster mushroom (Pleurotus ostreatus) in rabbits". Nahrung. 43 (5): 339–42. doi:10.1002/(SICI)1521-3803(19991001)43:5<339::AID-FOOD339>3.0.CO;2-5. PMID 10555301.
{{cite journal}}: Unknown parameter|month=ignored (help) - ^ Opletal L, Jahodár L, Chobot V; et al. (1997). "Evidence for the anti-hyperlipidaemic activity of the edible fungus Pleurotus ostreatus". Br. J. Biomed. Sci. 54 (4): 240–3. PMID 9624732.
{{cite journal}}: Explicit use of et al. in:|author=(help); Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Bajaj M, Vadhera S, Brar AP, Soni GL (1997). "Role of oyster mushroom (Pleurotus florida) as hypocholesterolemic/antiatherogenic agent". Indian J. Exp. Biol. 35 (10): 1070–5. PMID 9475042.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Bobek P, Ozdín L, Kuniak L, Hromadová M (1997). "[Regulation of cholesterol metabolism with dietary addition of oyster mushrooms (Pleurotus ostreatus) in rats with hypercholesterolemia]". Cas. Lek. Cesk. (in Slovak). 136 (6): 186–90. PMID 9221192.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Bobek P, Ozdín L, Kuniak L (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.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ 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.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ 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.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Bobek P, Ozdin L, Kuniak L (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.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ 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.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ 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.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Khatun K, Mahtab H, Khanam PA, Sayeed MA, Khan KA (2007). "Oyster mushroom reduced blood glucose and cholesterol in diabetic subjects". Mymensingh Med J. 16 (1): 94–9. PMID 17344789.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ 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.
- ^ http://www.nlm.nih.gov/medlineplus/ency/article/007115.htm Coronary heart disease: MedLine Plus Medical Encyclopedia
- ^ Endo, Akira (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.
{{cite journal}}: Unknown parameter|coauthors=ignored (|author=suggested) (help); Unknown parameter|month=ignored (help) - ^ 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.
- ^ Hirama M, Vet M (1982). "A chiral total synthesis of compactin". J. Am. Chem. Soc. 104: 4251. doi:10.1021/ja00379a037.
- ^ 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.
- ^ "Lovastatin". Rxlist.com.
- ^ 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.