History
Rosuvastatin, marketed as Crestor, is an HMG-CoA reductase inhibitor and a synthetic statin, a class of lipid-lowering drugs. Its development began with a research team at Shionogi & Co., Ltd. in Japan, aiming to develop a compound that was more effective and better tolerable than existing statins. The discovery and patent application of this compound are primarily attributed to Shionogi's team of chemists, with key inventors including Kentaro Hirai, Teruyuki Ishiba, Haruo Koike, and Masamichi Watanabe.
The discovery of this compound dates back to the early 1990s. In 1991, Shionogi successfully synthesized rosuvastatin and filed a patent application on July 1st of the same year. Rosuvastatin's unique molecular structure includes a sulfonamide group, giving it hydrophilicity, which is believed to contribute to its potential for liver selectivity and reduced muscle toxicity.
In the subsequent development and commercialization process, AstraZeneca granted AstraZeneca an exclusive global license for rosuvastatin. In 2003, rosuvastatin (Crestor) received approval from the U.S. Food and Drug Administration (FDA) for the treatment of hypercholesterolemia.
Uses
Rosuvastatin Calcium is a competitive inhibitor of HMG-CoA reductase with IC50 of 11 nM.
Definition
ChEBI: Rosuvastatin is a dihydroxy monocarboxylic acid that is (6E)-7-{4-(4-fluorophenyl)-2-[methyl(methylsulfonyl)amino]-6-(propan-2-yl)pyrimidin-5-yl} hept-6-enoic acid carrying two hydroxy substituents at positions 3 and 5 (the 3R,5S-diastereomer). It has a role as an antilipemic drug, an anti-inflammatory agent, a CETP inhibitor, a cardioprotective agent, a xenobiotic and an environmental contaminant. It is a member of pyrimidines, a sulfonamide, a dihydroxy monocarboxylic acid, a statin (synthetic) and a member of monofluorobenzenes. It derives from a hept-6-enoic acid. It is a conjugate acid of a rosuvastatin(1-).
Preparation
Rosuvastatin synthesis: Reduction to the 5-hydroxymethyl derivative proceeds smoothly with diisobutylaluminum hydride (DIBALH) in toluene at -10 °C. The hydroxymethyl group is then converted to the bromo derivative, which upon reaction with triphenylphosphine affords the Wittig reagent. The latter is treated with tert-butyl 2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate and provides the protected rosuvastatin ester. Removal of the dioxane protecting group by HCl, ester hydrolysis with NaOH and precipitation with CaCl2 gives rosuvastatin.
Kleemann A; Cardiovascular Drugs. Ullmann's Encyclopedia of Industrial Chemistry 7th ed. (1999-2017). NY, NY: John Wiley & Sons. Online Posting Date: January 15, 2008
Brand name
Crestor (AstraZeneca).
General Description
Rosuvastatin, 7-[4-(4-fluorophenyl)-6-(1-methylethyl)-2-(methyl-methylsulfonyl-amino)-pyrimidin-5-yl]-3,5-dihydroxy-hept-6-enoic acid (Crestor), is oneof the more recently introduced statins in the United States.As with all statins, there is a concern of rhabdomyolysis andas such, the FDA has mandated that a warning about thisside effect, as well as a kidney toxicity warning, be added tothe product label (http://www.fda.gov/CDER/Drug/advisory/crestor_3_2005.htm). This should not come as a surprisebecause of the relationship in the chemical architectureto cerivastatin, which was withdrawn from the market as aresult of its adverse side effects.
Clinical Use
HMG CoA reductase inhibitor:
Hyperlipidaemia
Metabolism
Rosuvastatin undergoes limited metabolism in the liver
mainly by the cytochrome P450 isoenzyme CYP2C9
(approximately 10%).
Approximately 90% of the rosuvastatin dose is excreted
unchanged in the faeces (consisting of absorbed and
non-absorbed active substance) and the remaining part is
excreted in urine.
