Rosuvastatin calcium

Description

Rosuvastatin, one of the two new statins launched for the treatment of hypercholesterolemia, has high hepato-selectivity and more potent inhibitory effect on HMG-CoA reductase than the previously marketed statins. In rat hepatocytes, it inhibits cholesterol biosynthesis with an IC₅₀ of 1.12 nM, which is ～100-fold higher potency than pravastatin. Rosuvastatin is synthesized in a 12-step sequence, entailing the construction of a pyrimidinyl aldehyde intermediate in eight steps and subsequent introduction of the dihydroxyheptenoate side chain via Wittig reaction with a bketophosphorane reagent and stereoselective carbonyl reduction of the resultant enone. Pharmacokinetic properties of rosuvastatin in humans, dosed at 5–80 mg, are approximately linear with dose. Following oral administration, rosuvastatin is rapidly absorbed with an oral bioavailability of ～20% and tmax of ～3 h. It has a prolonged duration of action, with terminal t_1/2 of ～20 h, compatible with once-daily dosing. In humans, rosuvastatin is minimally metabolized through CYP2C9 and CYP2C19, with little or no metabolism via the CYP3A4. Approximately 90% of the administered oral dose is eliminated in the feces (92% as the parent compound) and the rest in the urine. Rosuvastatin is considered a “superstatin” due to its ability, at well-tolerated doses, to lower LDL cholesterol and triglycerides to a much greater extent than first generation statins. In patients with hypercholesterolemia, rosuvastatin treatment at doses of 5 and 10 mg/day over 12-week period resulted in 40–43% reduction of LDL-cholesterol levels, 12–13% increase in HDL-cholesterol, and 17– 19% reduction in triglycerides. In comparison, the efficacy range of LDL-cholesterol reductions by atorvastatin (10 mg/day), pravastatin (20 mg/day), and simvastatin (20 mg/day) was 28–35%. Rosuvastatin is a well-tolerated drug at doses of 1–20 mg and the most common side effects at these doses are headache, myalgia, pain and pharyngitis, which are consistent with those previously reported for statin therapy.

Chemical properties

White to Off-White Crystalline Solid

Originator

Shinogi (Japan)

The Uses of Rosuvastatin calcium

Rosuvastatin Calcium Salt is a selective, competitive HMG-CoA reductase inhibitor. Antilipemic.

The Uses of Rosuvastatin calcium

antiinflammatory, glucocorticoid

The Uses of Rosuvastatin calcium

antirheumatic

What are the applications of Application

Rosuvastatin calcium is commonly used to lower bad cholesterol levels (LDL-C) and fats (triglycerides) in the blood. It also increases good cholesterol levels (HDL). Improving your cholesterol levels helps decrease your risk of heart disease, stroke, and heart attack.

Rosuvastatin calcium may also be used for other conditions as determined by your healthcare provider.

Definition

ChEBI: An organic calcium salt that is the hemicalcium salt of rosuvastatin.

brand name

Crestor (AstraZeneca).

General Description

Rosuvastatin calcium (ROS) has a molecular mass of 1001.14. ROS is a member of the "statins" group and is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor.

Biochem/physiol Actions

Rosuvastatin calcium is a competitive inhibitor of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonic acid, the rate-limiting step in cholesterol biosynthesis. Rosuvastatin calcium is antilipemic and is used to reduce plasma cholesterol levels and prevent cardiovascular disease.

Mechanism of action

Rosuvastatin is a statin medication and a competitive inhibitor of the enzyme HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase, which catalyzes the conversion of HMG-CoA to mevalonate, an early rate-limiting step in cholesterol biosynthesis.24 Rosuvastatin acts primarily in the liver, where decreased hepatic cholesterol concentrations stimulate the upregulation of hepatic low density lipoprotein (LDL) receptors which increases hepatic uptake of LDL. Rosuvastatin also inhibits hepatic synthesis of very low density lipoprotein (VLDL).44 The overall effect is a decrease in plasma LDL and VLDL.

Synthesis

The synthesis of optically pure rosuvastatin (23) begins from the Knoevenagel reaction of p-fluorobenzaldehyde (193) with ethyl isobutylacetate (194) to give unsaturated ketoester 195. Compound 195 was condensed with (S ) - methylisothiourea and then aromatized in situ using DDQ in methylene chloride to give pyrimidine 196 in 50% yield. Pyrimidine sulfide 196 was then oxided by m-CPBA to give sulfone 197 in 96% yield. Sulfone 197 was reacted with methylamine in methanol followed by treatment with methanesulfonyl chloride to give the N - methanesulfonylamino pyrimidine 198 in 58% yield. Reduction of ester 198 with DIBAL-H followed by TPAP oxidation afforded aldehyde 199 in 58% yield. Aldehyde 199 was subjected to Wittig reaction with optically pure ylide, (3R)-3-(t-butyldimethylsilyloxy)-5-oxo-6-triphenylphosphoranylidenehexanoate (200), to give heptenoate compound 201 in 71% yield. Compound 201 was deprotected with HF in acetonitrile, and stereoselective chelation-controlled reduction with Et2BOMe and NaBH4 in THF-MeOH mixed solvent gave methyl (3R, 5S, 6E)- dihydroxyheptenoate 202 in 85% yield. Diol 202 was hydrolyzed with aqueous NaOH to afford the corresponding sodium salt. Rosuvastatin calcium salt (23) was obtained as white powder from the sodium salt on treatment with aqueous CaCl2.

storage

Store at +4°C