Lipitor™

Many valuable compounds are aromatic in part, including steroids such as estrone and well-known pharmaceuticals such as the cholesterol-lowering drug alorvastatin, marketed as Lipitor. Benzene itself has been found to cause bone marrow depression and a consequent lowered white blood ceil count on prolonged exposure. Benzene should therefore be handled cautiously if used as a laboratory solvent. 

Discuss the important points to include in a teaching plan for a patient who is prescribed atorvastatin (Lipitor). 

The study concerns the desymmetrization of the prochiral dinitrile (16) with preferential formation of the (Ji)-17, which was known to be a chiral intermediate in the synthesis of the cholesterol-lowering therapeutic drug (18) (Lipitor, Sortis, Torvast, etc.) as shown in Scheme 2.3. 

Godecke Mack, Illert.) GB Lipitor (Parke Davis)... 

The cholesterol-lowering drug atorvastatin, marketed as Lipitor, is an example where biocatalysis research has been applied extensively and is in industrial use. The enzyme 2-deoxyribose-5-phosphate aldolase (DERA) has been a target of directed evolution for the production of atorvastatin intermediates [8,9,71]. DeSantis and coworkers [8,9] used structure-based... 

A summary of the industrial-scale process development for the nitrilase-catalyzed [93] route to ethyl (/ )-4-cyano-3-hydroxy-butyrate, an intermediate in the synthesis of Atorvastatin (Pfizer Lipitor) from epichlorohydrin via 3-hydroxyglutaronitrile (3-HGN) was recently reported (Figure 8.15) [94], The reaction conditions were further optimized to operate at 3 m (330 gL ) substrate, pH 7.5 and 27 °C. Under these conditions, 100% conversion and product ee of 99% was obtained in 16 h reaction time with a crude enzyme loading of 6% (based on total protein, 0.1 U mg-1). It is noted that at pH < 6.0 the reaction stalled at <50% conversion and at alkaline pH a slowing in reaction rate was observed. Since the starting material is of low cost and the nitrilase can be effectively expressed in the Pfenex (Pseudomonas) expression system at low cost, introduction of the critical stereogenic center... 

Lipitor (Atorvastatin) Atherosclerosis Dyslipidemia Hypercholesterolemia 3.8 1.3 1997 - UK and US Once daily... 

Case History In an attempt to protect Lipitor from generic competition, Pfizer sued Ranbaxy in district court asserting, in part, that Ranbaxy infringed upon dependent Claim 6 of U.S. Patent No. 5,273,995 ( 995). 

Analysis The active ingredient in Lipitor is atorvastatin calcium. Pfizer lost because of a deficiency in the way dependent Claim 6 related to Claims 1 and 2. The following chart is presented to help understand how this happened ... 

The recent years have seen the success of statins like Lipitor (atorvastatin) as hypolipidemic agents that help treating cardiovascular disease primarily by lowering low-density lipoproteins ( bad cholesterol ) levels. Another novel strategy is to tackle the same problem by elevating high-density lipoproteins (H D L or good cholesterol ) levels via inhibition of cholesteryl ester transfer protein (CETP). 

Baycol (cerivastatin, sold as Lipobay in Europe, Bayer) is a statin, a class of cholesterol-lower drugs. Statins are the most prescribed drugs in the United States, with more than 12 million people taking them, and more than 700,000 people in the United States taking cerivastatin. It received marketing approval on June 26, 1997 and was voluntarily removed from the market on August 8, 2001 because of its link to 100 deaths and several injuries from potentially the muscle disease rhabdomyolysis. The other statins — lovas-tatin (Mevacor Merck) pravastatin (Pravachol Bristol-Myers Squibb) simvastatin (Zocor Merck) fluvastatin (Lescol Novartis) atorvastatin (Lipitor Parke-Davis) rosuvastatin... 

Most of us are familiar with the effects of cholesterol. Exhibit 1.3 provides an explanation of how cholesterol is formed and the mechanism of action for Lipitor and Zocor in lowering the sterol. 

An enzyme (see Section 2.6) called HMG-CoA reductase is involved in the biosynthesis of cholesterol. Drugs such as atorvastatin (Lipitor) and simvastatin (Zocor) are competitive inhibitors of HMG-CoA reductase. They inhibit cholesterol synthesis by increasing the number of LDL receptors to take up the LDL. 

The top-selling drug in 2007 was Lipitor with about US 12 billion in sales and the top biopharmaceutical was Enbrel, which brings in about US 2.5 billion revenue. 

Atorvastatin (Lipitor, Pfizer) and simvastatin (Zocor, Merck) HMG-coenzyme A inhibitors for the reduction of cholesterol level in blood (refer to Exhibit 1.3). 

Atorvastatin (Lipitor, Pfizer) Cardiovascular Enzyme inhibitor... 

Lipitor (atorvastatin calcium) is a synthetic lipid-lowering drug. The chemical name for Lipitor is [R-(R, R )]-2-(4-fluorophenyl)-j3, 5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l-heptanoic acid, calcium salt (2 1) trihydrate. The molecular weight is 1209.42. It is a white... 

This cholesterol formation reaction is catalyzed by the enzyme HMG-CoA reductase. One means to stop or reduce the production of cholesterol is to interfere with the supply of mevalonate. This is the function of Lipitor, which acts as an inhibitor of HMG-CoA reductase. 

Lipitor enters the active site of the enzyme, blocking the entry of HMG-CoA, and hence denies it from being reduced and converted to mevalonate. The diagram below depicts the Lipitor molecule at the active site. 

Lipitor molecule at active site. Source. Istvan ES, Deisenhofer J. Structural mechanism for statin inhibition of HMG—CoA reductase, Science 292 1160 (2001). http //www.fda. gov/medwatch/SAFETY/2004/jul PI/Lipitor PI.pdf [accessed August 20, 2007]. Used with permission.)... 

Lipitor recall in Spring 2003—millions of fake pills were smuggled into the United States from abroad. The Lipitor case highlights the problem of increasing and increasingly sophisticated counterfeit drugs. 

The most important class of cholesterol-lowering agents is the statins. These include lovastatin (Mevacor), simvastatin (Zocor), pravastatin (Pravachol), and atorvastatin (Lipitor), among others. These molecules work, in modest part, by inhibiting biosynthesis of cholesterol and, in larger part, by increasing the rate at which cholesterol is eliminated by the body. Let s have a look at this in more detail. 

For certain kinds of data sets, only the molecular structure makes sense, for example, databases of synthetic reactions. For a few others, only the salt form makes sense, for example, when you buy Lipitor or dispense it to a patient, what does 100 mg of Lipitor mean For the remaining, the molecular and salt forms are synonymous. 

Two communication languages used by Cabinet are SMILES and ECN (En2yme Commission Number). When one Cabinet server asks another, What do you know about Lipitor , it is asking about SMILES ... 

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