Statins Alcohol

Specific concomitant medications or consumptions (check specific statin package insert for warnings) fibrates (especially gemfibrozil, but other fibrates too), nicotinic acid (rarely), cyclosporine, azole antifungals such as itraconazole and ketoconazole, macrolide antibiotics such as erythromycin and clarithromycin, protease inhibitors used to treat Acquired Immune Deficiency Syndrome, nefazodone (antidepressant), verapamil, amiodarone, large quantities of grapefruit juice (usually more than 1 quart per day), and alcohol abuse (independently predisposes to myopathy)... 

BINAP-Ru is effective for the diastereoselective hydrogenation of some chiral yS-keto esters (Fig. 32.13). Reaction of N-Boc-protected (S)-y-amino / -keto esters 13A catalyzed by the (R)-BINAP-Ru complex results in the syn alcohols 13B exclusively [52]. The stereocenter at the / -position is controlled by the chirality of the catalyst therefore, use of the S catalyst affords the anti isomer, as predicted. Derivatives of statine, a key component of the aspartic proteinase inhibitor pep-... 

Asymmetric hydrogenation of ketones is one of the most efficient methods for making chiral alcohols. Ru-BINAP catalysts are highly effective in the asymmetric hydrogenation of functionalized ketones,54,55 and this may be used in the industrial production of synthetic intermediates for some important antibiotics. The preparation of statine 65 (from 63b R = i-Bu) and its analog is one example (Scheme 6-28).56 Table 6-6 shows the results when asymmetric hydrogenation of 63 catalyzed by RuBr2[(R)-BINAP] yields threo-64 as the major product. 

Simvastatin, a conjugated alkene, can polymerise as a result of peroxyl radical addition. The peroxide-linked oligomers can be subsequently cleaved to produce epoxides, which in turn degrade to form ketones and alcohols [69]. Inclusion of vitamin E (a-tocopherol) into formulations was found to inhibit chain-oxidation of simvastatin, lovastatin and other structurally related statins. 

The statine residue mimics the noncovalently bonded tetrahedral intermediate, permitting formation of a very tight complex. Pepstatin is a poor inhibitor of human renin but its existence has inspired the synthesis of numerous related compounds, some of which are effective renin inhibitors/ Some of these inhibitors use the human angiotensinogen sequence with a secondary alcohol group mimicking the tetrahedral intermediate/ 2... 

Another way to statin side chains, via the intermediate syn-(i K,5,S )-6-chloro-hexanoate, employs regioselective and (K)-specific reduction with alcohol dehydrogenase (ADH) from Lactobacillus brevis to yield the intermediate (5S)-6-chloro-3-ketohexanoate from the 3,5-diketo acid (Wolberg, 2001) (Figure 13.16). Further reduction of (5S)-6-chloro-3-ketohexanoate to syn-(3R,5S)-6-chlorohexanoate is afforded chemically with NaBH4/B(OMe)Et2. 

Wolberg M, Filho M et al (2008) Chemoenzymatic synthesis of the chiral side-chain of statins application of an alcohol dehydrogenase catalysed ketone reduction on a large scale. Bioprocess Biosyst Eng 31 183-191... 

Alcohol Dehydrogenase Catalyzed Synthesis of the Chiral Side Chain of Statins... 

Anfossi G, Massucco P, Bonomo K, Trovati M (2004) Prescription of statins to dyslipidemic patients affected by liver diseases a subtle balance between risks and benefits. Nutr Metab Cardiovasc Dis 14 215-224. Gomez-Dominguez E, Gisbert J, Moreno-Monteagudo J, Garcia-Buey L, Moreno-Otero R (2006) A pilot study of atorvastatin treatment in dys-lipemid, non-alcoholic fatty liver patients. Aliment Pharmacol Ther 23 1643-1647. 

Clinically important, potentially hazardous interactions with alcohol, CNS depressants, erythromycin, grapefruit juice, ketoconazole, statins... 

Cirrhosis of the liver is one of the most well-known adverse effects of chronic alcohol abuse. The cholesterol-lowering, life-prolonging statin drugs must be monitored routinely for hepatotoxicity and rhabdomyolosis. A Google search on the terms statins, hepatotoxicity, and review produced over 22,000 hits indicating this is a very active field of interest. 

Two different approaches to ( —)-statine (831), an unusual amino acid component of pepstatine, both employ 793c as their starting point. In the first synthesis (Scheme 120) [183], reduction of 793c with sodium borohydride produces a mixture of two isomeric 5-hydroxy-pyrrolidinones, from which the pure cis product 824 crystallizes in 85% yield. Conversion of bisacetate 825 to thioether 826 followed by removal of the acetate and silylation of the resulting alcohol affords 827. Radical cyclization of 827 produces a 3 2 mixture of isomers 828. Desilylation and debenzylation gives 829 as a single diastereomer. The Boc-protected intermediate 830 intersects with a known synthesis of ( —)-statine (831). 

Alcoholics are susceptible to drug toxicity, because alcohol induces liver injury and cirrhotic changes that alter drug metabolism. Alcohol causes depletion of glutathione (hepatoprotective) stores, making the person more susceptible to toxicity by drugs (e.g., acetaminophen, statins). 

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