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 t1/2 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.
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.
