Triparanol

Last updated
Triparanol
Triparanol.svg
Clinical data
Trade names MER/29
Other namesMetasqualene
ATC code
  • None
Identifiers
  • 2-(4-Chlorophenyl)-1-[4-[2-(diethylamino)ethoxy]phenyl]-1-(4-methylphenyl)ethanol
CAS Number
PubChem CID
ChemSpider
UNII
ChEBI
CompTox Dashboard (EPA)
ECHA InfoCard 100.001.014 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C27H32ClNO2
Molar mass 438.01 g·mol−1
3D model (JSmol)
  • CCN(CC)CCOc1ccc(C(O)(Cc2ccc(Cl)cc2)c2ccc(C)cc2)cc1
  • InChI=1S/C27H32ClNO2/c1-4-29(5-2)18-19-31-26-16-12-24(13-17-26)27(30,23-10-6-21(3)7-11-23)20-22-8-14-25(28)15-9-22/h6-17,30H,4-5,18-20H2,1-3H3
  • Key:SYHDSBBKRLVLFF-UHFFFAOYSA-N

Triparanol (INN, BAN; brand name and development code MER/29, as well as many other brand names) was the first synthetic cholesterol-lowering drug. [1] [2] It was patented in 1959 and introduced in the United States in 1960. [3] [4] The developmental code name of triparanol, MER/29, became so well known that it became the registered trade name of the drug. [5] It was withdrawn in 1962 due to severe adverse effects such as nausea and vomiting, vision loss due to irreversible cataracts, alopecia, skin disorders (e.g., dryness, itching, peeling, and "fish-scale" texture), and accelerated atherosclerosis. [3] [2] It is now considered to be obsolete. [3] [2]

The drug acts by inhibiting 24-dehydrocholesterol reductase, which catalyzes the final step of cholesterol biosynthesis, the conversion of desmosterol into cholesterol. [6] Although effective in reducing cholesterol levels, this results in tissue accumulation of desmosterol, which in turn is responsible for the side effects of triparanol. [2] Unlike statins, triparanol does not inhibit HMG-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis, [2] and in contrast to triparanol, statins can lower cholesterol levels without resulting in accumulation of intermediates like desmosterol. [2]

Estrogen is known to lower cholesterol levels, but produces side effects like gynecomastia and decreased libido in men. [3] It was hoped that a drug could be developed that lacked overt estrogenic effects but still lowered cholesterol levels. [3] Triparanol is a triphenylethanol and was derived from chlorotrianisene (TACE), a nonsteroidal triphenylethylene estrogen. [3] [7] The nonsteroidal triphenylethanol antiestrogen ethamoxytriphetol (MER-25) is a derivative of triparanol. [8] The selective estrogen receptor modulator clomifene is also structurally related to triparanol. [7] [9] The developers of triparanol jokingly referred to it as a "non-estrogenic estrogen" due to its lipid-lowering effects without other estrogenic effects. [3]

See also

Related Research Articles

<span class="mw-page-title-main">Cholesterol</span> Sterol biosynthesized by all animal cells

Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol, a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell membranes. When chemically isolated, it is a yellowish crystalline solid.

<span class="mw-page-title-main">Statin</span> Class of drugs used to lower cholesterol levels

Statins, also known as HMG-CoA reductase inhibitors, are a class of lipid-lowering medications that reduce illness and mortality in those who are at high risk of cardiovascular disease. They are the most common cholesterol-lowering drugs.

Lipid-lowering agents, also sometimes referred to as hypolipidemic agents, cholesterol-lowering drugs, or antihyperlipidemic agents are a diverse group of pharmaceuticals that are used to lower the level of lipids and lipoproteins such as cholesterol, in the blood (hyperlipidemia). The American Heart Association recommends the descriptor 'lipid lowering agent' be used for this class of drugs rather than the term 'hypolipidemic'.

<span class="mw-page-title-main">Atorvastatin</span> Cholesterol-lowering medication

Atorvastatin, sold under the brand name Lipitor among others, is a statin medication used to prevent cardiovascular disease in those at high risk and to treat abnormal lipid levels. For the prevention of cardiovascular disease, statins are a first-line treatment. It is taken by mouth.

<span class="mw-page-title-main">Simvastatin</span> Lipid-lowering medication

Simvastatin, sold under the brand name Zocor among others, is a statin, a type of lipid-lowering medication. It is used along with exercise, diet, and weight loss to decrease elevated lipid levels. It is also used to decrease the risk of heart problems in those at high risk. It is taken by mouth.

<span class="mw-page-title-main">Fluvastatin</span> Chemical compound

Fluvastatin is a member of the statin drug class, used to treat hypercholesterolemia and to prevent cardiovascular disease.

<span class="mw-page-title-main">Pravastatin</span> Cholesterol lowering medication in the statin class

Pravastatin, sold under the brand name Pravachol among others, is a statin medication, used for preventing cardiovascular disease in those at high risk and treating abnormal lipids. It should be used together with diet changes, exercise, and weight loss. It is taken by mouth.

<span class="mw-page-title-main">Lovastatin</span> Chemical compound

Lovastatin, sold under the brand name Mevacor among others, is a statin medication, to treat high blood cholesterol and reduce the risk of cardiovascular disease. Its use is recommended together with lifestyle changes. It is taken by mouth.

<span class="mw-page-title-main">Cerivastatin</span> Chemical compound

Cerivastatin is a synthetic member of the class of statins used to lower cholesterol and prevent cardiovascular disease. It was marketed by the pharmaceutical company Bayer A.G. in the late 1990s, competing with Pfizer's highly successful atorvastatin (Lipitor). Cerivastatin was voluntarily withdrawn from the market worldwide in 2001, due to reports of fatal rhabdomyolysis.

<span class="mw-page-title-main">HMG-CoA reductase</span> Mammalian protein found in Homo sapiens

HMG-CoA reductase is the rate-controlling enzyme of the mevalonate pathway, the metabolic pathway that produces cholesterol and other isoprenoids. HMGCR catalyzes the conversion of HMG-CoA to mevalonic acid, a necessary step in the biosynthesis of cholesterol. Normally in mammalian cells this enzyme is competitively suppressed so that its effect is controlled. This enzyme is the target of the widely available cholesterol-lowering drugs known collectively as the statins, which help treat dyslipidemia.

Hyperlipidemia is abnormally elevated levels of any or all lipids or lipoproteins in the blood. The term hyperlipidemia refers to the laboratory finding itself and is also used as an umbrella term covering any of various acquired or genetic disorders that result in that finding. Hyperlipidemia represents a subset of dyslipidemia and a superset of hypercholesterolemia. Hyperlipidemia is usually chronic and requires ongoing medication to control blood lipid levels.

<span class="mw-page-title-main">Pitavastatin</span> Chemical compound

Pitavastatin is a member of the blood cholesterol lowering medication class of statins.

The discovery of HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) reductase inhibitors, called statins, was a breakthrough in the prevention of hypercholesterolemia and related diseases. Hypercholesterolemia is considered to be one of the major risk factors for atherosclerosis which often leads to cardiovascular, cerebrovascular and peripheral vascular diseases. The statins inhibit cholesterol synthesis in the body and that leads to reduction in blood cholesterol levels, which is thought to reduce the risk of atherosclerosis and diseases caused by it.

<span class="mw-page-title-main">Lapaquistat</span> Chemical compound

Lapaquistat (TAK-475) is a cholesterol-lowering drug candidate that was abandoned before being marketed.

<span class="mw-page-title-main">Desmosterolosis</span> Medical condition

Desmosterolosis in medicine and biology is a defect in cholesterol biosynthesis. It results in an accumulation of desmosterol and a variety of associated symptoms. Only two cases have been reported as of 2007. The condition is due to inactivating mutations in 24-dehydrocholesterol reductase. Certain anticholesterolemic and antiestrogenic drugs such as triparanol, ethamoxytriphetol, and clomifene have been found to inhibit conversion of desmosterol into cholesterol and to induce desmosterolosis, for instance cataracts.

<span class="mw-page-title-main">Azacosterol</span> Chemical compound

Azacosterol (INN), or azacosterol hydrochloride (USAN), also known as 20,25-diazacholesterol, is a cholesterol-lowering drug (hypocholesteremic), which was marketed previously, but has since been discontinued. It is also an avian chemosterilant used to control pest pigeon populations via inducing sterility. The drug is a sterol and derivative of cholesterol in which two carbon atoms have been replaced with nitrogen atoms.

<span class="mw-page-title-main">Triphenylethylene</span> Chemical compound

Triphenylethylene (TPE) is a simple aromatic hydrocarbon that possesses weak estrogenic activity. Its estrogenic effects were discovered in 1937. TPE was derived from structural modification of the more potent estrogen diethylstilbestrol, which is a member of the stilbestrol group of nonsteroidal estrogens.

<span class="mw-page-title-main">Ethamoxytriphetol</span> Chemical compound

Ethamoxytriphetol is a synthetic nonsteroidal antiestrogen that was studied clinically in the late 1950s and early 1960s but was never marketed. MER-25 was first reported in 1958, and was the first antiestrogen to be discovered. It has been described as "essentially devoid of estrogenic activity" and as having "very low estrogenic activity in all species tested". However, some estrogenic effects in the uterus have been observed, so it is not a pure antiestrogen but is, instead, technically a selective estrogen receptor modulator (SERM). For all intents and purposes, it is a nearly pure antiestrogen, however.

A steroidogenesis inhibitor, also known as a steroid biosynthesis inhibitor, is a type of drug which inhibits one or more of the enzymes that are involved in the process of steroidogenesis, the biosynthesis of endogenous steroids and steroid hormones. They may inhibit the production of cholesterol and other sterols, sex steroids such as androgens, estrogens, and progestogens, corticosteroids such as glucocorticoids and mineralocorticoids, and neurosteroids. They are used in the treatment of a variety of medical conditions that depend on endogenous steroids.

<span class="mw-page-title-main">Colestolone</span> Chemical compound

Colestolone, also known as 5α-cholest-8(14)-en-3β-ol-15-one, is a potent inhibitor of sterol biosynthesis which is described as a hypocholesterolemic (lipid-lowering) agent. It was first reported in 1977 and was studied until at least 1988, but was never introduced for medical use.

References

  1. ↑ Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 1252–. ISBN   978-1-4757-2085-3.
  2. 1 2 3 4 5 6 Ravina E (11 January 2011). The Evolution of Drug Discovery: From Traditional Medicines to Modern Drugs. John Wiley & Sons. pp. 178–. ISBN   978-3-527-32669-3.
  3. 1 2 3 4 5 6 7 Li JJ (3 April 2009). Triumph of the Heart: The Story of Statins. Oxford University Press, USA. pp. 33–. ISBN   978-0-19-532357-3.
  4. ↑ Vance DE, Vance JE (200). Biochemistry of Lipids, Lipoproteins, and Membranes. Elsevier. pp. 172–174. ISBN   978-0-444-51138-6.
  5. ↑ Miller LC (July 1961). "Doctors, drugs, and names". JAMA. 177 (1): 27–33. doi:10.1001/jama.1961.73040270014004b. PMID   13770852. Recently, another laboratory code number, MER29, became so well known that it was adopted as the registered trademark for the anticholesterolemic drug concerned (triparanol).
  6. ↑ Burtis CA, Ashwood ER, Bruns DE (14 October 2012). Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. Elsevier Health Sciences. pp. 733–. ISBN   978-1-4557-5942-2.
  7. 1 2 Grant WM, Schuman JS (1 January 1993). TOXICOLOGY OF THE EYE: Effects on the Eyes and Visual System from Chemicals, Drugs, Metals and Minerals, Plants, Toxins and Venoms; also Systemic Side Effects from Eye Medications (4th Ed.). Charles C Thomas Publisher. pp. 384–. ISBN   978-0-398-08215-4.
  8. ↑ Manni A (15 January 1999). Endocrinology of Breast Cancer. Springer Science & Business Media. pp. 286–. ISBN   978-1-59259-699-7.
  9. ↑ Aronson JK (21 February 2009). Meyler's Side Effects of Endocrine and Metabolic Drugs. Elsevier. pp. 163–. ISBN   978-0-08-093292-7.
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