Anticholesterol drug

A key driver of success in the OTC market is the ability to capitalize on the brand loyalty enjoyed by the prescription product. The number of category shifts to OTC status approved by the FDA has grown over time. At the same time, there are many therapeutic categories where this is not as viable strategy because they would not meet the FDA s requirement on safety for self-medication (e.g., mental health and cancer drugs). The FDA has also declined several product requests for shifts to OTC status, such as anticholesterol drug agents. 

An example of the value-added chain extending from commodities through fine chemicals to a pharmaceutical specialty is shown in Table 1.1. The product chosen is Pfizer s anticholesterol drug Lipitor (atorvastatin), the world s top-selling drug with sales of 12 billion in 2004. The value-added chain extends from a Ci molecule, methanol (left side of the table) all the way to a C33 molecule, atorvastatin. The structure of compound III in Table 1.1 is as follows ... 

An example is the AstraZenecas anticholesterol drug Crestor (rosuvastatin). Although the patent expires only in 2012, there are already about 25 manufacturers in India, including famous names such as Ranbaxy (Rosuvas) and Dr Reddy s Laboratories (Rosvat). 

Invented by Bruce Roth in the late 1980s and now sold by Pfizer, the anticholesterol drug Lipitor became the world s best-selling drug. This article tells the story of the drug s development and success. 

Synthesis of a Chiral R-[+) Hydromethyl Glutaryl Coenzyme A Reductase Inhibitor (Anticholesterol Drug)... 

Figure 13 Synthesis of chiral synthon for anticholesterol drug SQ 33600 stereoselective microbial reduction of 4-chloro-3-oxobutanoic acid methyl ester (39).

So far, most microorganisms and enzymes derived therefrom have been used in the reduction of a single keto group of p-keto or a-keto compounds [68-71], Recently, Patel et al. [72] have demonstrated the stereoselective reduction of 3,5-dioxo-6-(benzyloxy)hexanoic acid, ethyl ester (41), to (3,S, 5R)-dihydroxy-6-(benzyloxy)hexanoic acid, ethyl ester (42a) (Fig. 14). The compound (42a) is a key chiral intermediate required for the chemical synthesis of [4-[4a,6P(E)]]-6-[4,4-bis(4-fluorophenyl)-3-(l-methyl-lH-tetrazol-5-yl)-l,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one, compound R-( + )-(43), a new anticholesterol drug that acts by inhibition of HMG CoA reductase [73], Among various microbial cultures evaluated for the stereoselective reduction of diketone (41), cell suspensions of Aci-... 

Pravastatin (47) and Mevastatin (48) are anticholesterol drugs which act by competitively inhibiting HMG Co A reductase [75], Pravastatin sodium is produced by two fermentation steps. The first step is the production of compound ML-236B by Penicillium citrinum [75-77], The purified compound was con-... 

Figure 15 Synthesis of chiral anticholesterol drug 43) stereoselective...

Vinylation of the triple bond is used industrially for the synthesis of Terbinafin, an anticholesterol drug possessing selective inhibiting activity on squalene... 

Benzyloxy-(3f ,5S)-dihydroxy-hexanoic acid ethyl ester is a key chiral intermediate for anticholesterol drugs that act by inhibition of hydroxy methyl glutaryl coenzyme A (HMG CoA) reductase. 

Figure 19-3. Synthesis of key intermediate of anticholesterol drugs (Bristol-Myers Squibb).

Another example of an a,a-disubstituted a-amino acid to be accessed by resolution is R)-2-amino-2-ethylhexanoic acid (3), a building block for the anticholesterol drug 2164U90 (4) (Scheme... 

ANTICHOLESTEROL DRUGS HYDROXYMETHYL GLUTARYL CoA REDUCTASE INHIBITORS... 

FIGURE 16.16 Anticholesterol drug 60. Preparation of (5)-4-chloro-3-hydroxybutanoic acid methyl ester 59. 

FIGURE 16.17 Anticholesterol drug 64. Diastereoselective enzymatic reduction of 3,5-dioxo-6-(benzyloxy) hexanoic acid, ethyl ester 62. 

The (5i, 3i )-alcohol 54a, [4-[4a,6fi(E)]]-6-[4, 4-bis[4-fluorophenyl)-3-(l-methyl-lH-tetrazol-5-yl)-l,3-butadienyl]tetrahydro-4-hydroxy-2H-pyren-2-one (Figure 11.14) is a potential new anticholesterol drug which acts by inhibition... 

Ethyl (3R,5S)-dihydroxy-6-(benzyloxy)hexanoate 72 (Figure 11.1) is a key chiral intermediate for the s)mthesis of Atorvastatin 12, and Rosuvastatin 13, anticholesterol drugs that act by inhibiting HMG CoA reductase [132-134]. The enantioselective reduction of a diketone, ethyl 3,5-dioxo-6-(benzyloxy) hexanoate 73 to ethyl (3R,5S)-dihydroxy-6-(benzyloxy) hexanoate 72 (Figure 11.21) was demonstrated by cell suspensions of Acinetobacter calcoace-ticus sc 13876 [135,136]. On reduction of 73 by cell suspensions, the syn-4 and anti-8 dihydroxy esters were formed in the ratio of about 87 13, 83 17, 76 24 after 24 h at 2, 5 and 10 g/L of substrate input, respectively. There was no significant peak due to a monohydroxy ester. Chiral HPLC determined that the desired syn-(3R,5S)-72 was the major product wdth 99.4% ee. Almost complete (>95%) conversion of the diketoester 73 to dihydroxy ester 72 in 24 h... 

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