3- Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors

Statins (3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors)... 

During the preparation of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, the benzyl ester protecting group was removed by catalytic hydrogenolysis (Scheme 4.42). 

There is interest in the use of lipid-lowering agents, especially the 3-hydroxy-3-methylglutaryl coenzyme A-reductase inhibitors, to prevent AD. Pravastatin and lovastatin, but not simvastatin, were associated with a lower prevalence of AD. Further study is needed before these agents can be recommended for this use. 

Fischer, V., Johanson, L., Heitz, F., Tullmann, R., Graham, E., Baldeck, J.P. and Robinson, W.T., The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor fluvastatin effect on human cytochrome P-450 and implications for metabolic drug interactions. Drug Metab. Dispos., 1999, 27, 410 16. 

Thieno[2,3-. ]pyridine derivatives, 155, can be successfully used as replacements for the hexahydronaphthalene ring found in naturally occurring 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors <2001BML1285>. These compounds also display significant inhibition of cholesterol biosynthesis in vivo. 

Polonsky TS, Davidson MH Reducing the residual risk of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor therapy with combination therapy. Am 3 Cardiol 2008 101(Suppl) 27B. 

SY Sit, RA Parker, I Motoe, HW Balsubramanian, CD Cott, PJ Brown, WE Harte, MD Thompson, J Wright. Synthesis, biological profile, and quantitative structure-activity relationship of a series of novel 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. J Med Chem 33 2982-2999, 1990. 

Blanco-Colio LM, Munoz-Garcia B, Martin-Ventura JL, et al. 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors decrease Fas ligand expression and cytotoxicity in... 

Jacobsen W, Kirchner G, Hallensleben K, et al. Small intestinal metabolism of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor lovastatin and comparison with pravastatin. J Pharmacol Exp Ther 1999 291(1) 131—139. 

Lactone 7 can serve as a versatile starting material for the synthesis of a range of HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors, commonly referred to as statins, which includes Lipitor (8) and Crestor (9) compounds (Scheme 20.7). In a single transformation, the lactone ring can be opened and the chloride can be displaced by either cyanide or hydroxide to access advanced Lipitor or Crestor intermediates, respectively. 

Lipitor (l)2 is a cholesterol-lowering agent whose mode of action is as an HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitor. It has been marketed by Pfizer and is sold as the calcium salt. 

Willey, J.Z., and Elkind, M.S. (2010). 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors in the treatment of central nervous system diseases. Arch Neurol 67 1062-1067. 

Miyake, Y., Shouzu, A., Nishikawa, M., Yonemoto, T., Shimizu, H., Omoto, S., Hayakawa, T., and Inada, M. (1999). Effect of treatment with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on serum coenzyme QIO in diabetic patients. Arznei-mittelforschung 49 324-329. 

Hsyu PH, Schultz-Smith MD, Lillibridge JH, Lewis RH, Kerr BM. Pharmacokinetic interactions between nelfinavir and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors atorvastatin and simvastatin. Antimicrob Agents Chemother 2001 45(12) 3445-50. 

Sica DA, Gehr TW (2002) 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors and rhabdomyolysis considerations in the renal failure patient. Curr Opin Nephrol Hypertens 11 123-133... 

Stokker GE, Hoffman WF, Alberts AW, et al. 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors. 1. Structural modification of 5-substituted 3,5-dihydroxypentanoic acids and their lactone derivatives. J Med Chem 1985 28 347-358. 

Chen XR, Besson VC, Beziand T, Plotkine M, Marchand-Leroux C (2008b) Combination therapy with fenofibrate, a peroxisome proUferator-activated receptor alpha agonist, and simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, on experimental traumatic brain injury. J Pharmacol Exp Ther 326 966-974... 

A representative publication using these methods is a study in which lipophilicities and solubilities were measured for four 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors by LC. Partition coefficients were determined in this study by LC analysis of drug content in the aqueous phase before and after equilibration with n-octanol and were then compared to retention factors in a reversed-phase LC system. The hydroxyacid form of pravastatin was found to have the lowest oil in water partition coefficient (P o/w) with simvastatin the highest. 

Fluvastatin is a totally synthesised 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor and has clinical anti-hypercholesterolaemic effects (Kathawala 1991). The anti-atherogenic properties of fluvastatin may not be limited to its hypo-cholesterolaemic, but may also be related to its ability to reduced low-density hpoprotein oxidizabihty (Hussein etal. 1997, Bellosta etal. 1998). Antioxidant effects of fluvastatin have also been reported in humans (Hussein etal. 1997, Leon-HARDT et al. 1997, Bellosta et al. 1998) and rabbits (Bandoh et al. 1996, Mitani et al. 1996). 

---