Natural Cholesterol Guide

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Rosuvastatin 8 (Figure 7) contains an unusual N-methyl N-linked sulfonamide moiety in addition to its fully substituted pyrimidine core,67 while retaining the unsaturated E-heptenoic acid side chain with the identical (3R, 5S) chirality found in fluvastatin. Rosuvastatin 26a was more potent in vitro (IC50 = 0.16 nM) than any of the related pyrimidine 26b-26g or pyrrole 27a and 27b analogs (Figure 11) tested, being approximately 10-fold more potent in vitro than atorvastatin. The x-ray structure of enzyme-bound rosuvastatin revealed that it generated the most ligand-protein interactions of any of the statins studied crystallographically.60 The combination of the pyrimidine ring and the sulfonamide moiety serves to lower dramatically the clogP of rosuvastatin to — 0.3, near that of pravastatin. As such, rosuvastatin is the most hydrophilic synthetic statin reported.

Rosuvastatin reduced total plasma cholesterol in beagle dogs by 26% after 14 days of oral dosing at 3 mgkg — 1 day — 1 compared to an 18% reduction obtained with 3 mgkg— 1 day— 1 of pravastatin. In cynomolgus monkeys, rosuvastatin reduced plasma cholesterol by 22% at a daily oral dose of 12.5 mgkg— 1, comparable to the effects obtained with a 50 mgkg — 1 day — 1 oral dose of pravastatin that reduced cholesterol by 19%. The overall bioavailability of rosuvastatin is b 20%, exceeding that of atorvastatin. The greater polarity associated with rosuvastatin results in reduced protein binding (88%) compared with other synthetic statins. Interestingly, rosuvastatin, like pravastatin, is not metabolized significantly by CYP enzymes, including CYP3A4, so the drug-drug interaction potential is reduced. Rosuvastatin is slowly metabolized by CYP2C9 and CYP2C19 to generate small quantities of the corresponding N-desmethyl derivative. Rosuvastatin has a prolonged duration of action and a longer plasma half-life (t1/2 = 20 h) in humans than any other statin. Rosuvastatin 8 was first approved for human use in the US and Europe in 2003.

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