ATORVASTATIN

ATORVASTATIN

CAS Number:134523-00-5
Molecule Formula:C33H35FN2O5
Molecular Weight:558.650 g·mol−1

Atorvastatin, sold under the brand name Lipitor among others, is a statin medication used to prevent cardiovascular disease in those at high risk and to treat abnormal lipid levels. 
For the prevention of cardiovascular disease, statins are a first-line treatment. 
It is taken by mouth. 

-History-
Bruce Roth, who was hired by Warner-Lambert as a chemist in 1982, had synthesized an "experimental compound" codenamed CI 981 – later called atorvastatin. 
It was first made in August 1985. 
Warner-Lambert management was concerned that atorvastatin was a me-too version of rival Merck & Co.'s orphan drug lovastatin (brand name Mevacor). 
Mevacor, which was first marketed in 1987, was the industry's first statin and Merck's synthetic version – simvastatin – was in the advanced stages of development. 
Nevertheless, Bruce Roth and his bosses, Roger Newton and Ronald Cresswell, in 1985, convinced company executives to move the compound into expensive clinical trials. 
Early results comparing atorvastatin to simvastatin demonstrated that atorvastatin appeared more potent and with fewer side effects.

In 1994, the findings of a Merck-funded study were published in The Lancet concluding the efficacy of statins in lowering cholesterol proving for the first time not only that a "statin reduced 'bad' LDL cholesterol but also that it led to a sharp drop in fatal heart attacks among people with heart disease."

In 1996, Warner-Lambert entered into a co-marketing agreement with Pfizer to sell Lipitor, and in 2000, Pfizer acquired Warner-Lambert for $90.2 billion. 
Lipitor was on the market by 1996. By 2003, Lipitor had become the best selling pharmaceutical in the United States. 
From 1996 to 2012, under the trade name Lipitor, atorvastatin became the world's best-selling medication of all time, with more than $125 billion in sales over approximately 14.5 years.
Lipitor alone "provided up to a quarter of Pfizer Inc.'s annual revenue for years."
Pfizer's patent on atorvastatin expired in November 2011.

-Manufacturing Process- 
285 ml 2.2 M n-butyl lithium in hexane was added dropwise to 92 ml diisopropylamine at -50-60°C under nitrogen. 
The well stirred solutions warmed to about -20°C, then it was cannulated into a suspension of 99 g of S(+)-2-acetoxy-1,1,2-triphenylethanol in 500 ml absolute tetrahydrophuran (THF) at -70°C and the reaction mixture was allowed to warm to -10°C for 2 hours. 
A suspension of MgBr2 was made from 564 ml (0.63 mol) of bromine and 15.3 g of magnesium (0.63 mol) in 500 ml THF cooled to -78°C. 
The enolate solution was cannulated into this suspension within 30 min and was stirred for 60 min at -78°C. 150 g 5-(4-fluorophenyl)-2-(1-methylethyl)-1-(3- oxopropyl)-N,4-diphenyl-1H-pyrrole-3-carboxamide in 800 ml absolute THFwas added dropwise over 30 min, stirred 90 min at -78°C, then was added 200 ml acetic acid, this is removed to a cool bath, 500 ml of H2O was added and the mixture concentrate in vacuo at 40-50°C. 
After adding of 500 ml of 1:1 EtOAc/heptane the mixture was filtered. 
The filtrate was washed extensively with 0.5 N HCl, then several times with H2O and finally EtOAc/heptane (3:1) and cooled with dry ice to -20°C. 
The light brown crystalline product was dried in vacuum oven at 40°C. 
The yield was 194 g. 
112 g of the same product was produced by evaporation of mother liquor after recrystallization and chromatographic purification on a silicagel.
162 g of this substance was suspended in methanol/THF (5:3) and was stirred with 11.7 g of sodium methoxide until everything was dissolved and kept in the freezer overnight. 
Later it was quenched with AcOH concentrated in vacuo, was added to 500 ml H2O and extracted twice with EtOAc (300 ml). 
The combined extracts was washed with saturated NaHCO3 brine and dried over anhydrous MgSO4, purified on silica-gel and gave 86.1 g of white crystals m.p. 125-126°C, αD 20=4.23° (1.17 M, CH3OH).
81 g of the last product in 500 ml absolute THF was added as quickly as possible to the mixture of 77 ml THF at diisopropylamine, 200 ml 2.2 M of nbutyl lithium and 62 ml of t-butylacetate in 200 ml THF -40-42°C under nitrogen. 
Stirring was continued for 4 hours at -70°C. The reaction mixture was concentrated in vacuo, the residue was taken up in EtOAc, washed with water, then saturated NH4Cl, NaHCO3 (saturated), dried over anhydrous MgSO4, filtred and the solvent evaporated.
The organic phase was dried and concentrated in vacuo to yield 73 g crude product, that was dissolved in 500 ml absolute THF, 120 ml triehtylborane and 0.7 g t-butylcarboxylic acid, 70 ml methanol and 4.5 g sodium borohydride was added. 
The mixture was stirred at -78°C under a dry atmosphere for 6 hours, poured slowly into 4:1:1 mixture of ice/30%H2O2/H2O and stirred overnight. 
CHCl3 (400 ml) was added and organic layer washed extensively with H2O until no peroxide could be found, was dried over MgSO4, filtered and was treated by chromatography on silica gel to yield 51 g. 
The product was dissolved in THF/methanol and saponificated with NaOH and, concentrated to remove organic solvents at room temperature, added 100 ml H2O, and extracted with Et2O twice. 
Organic layer was thoroughly dried and it was left at room temperature for the next 10 days, then concentrated.
Chromatography on silica gel yielded 13.2 g racemate of lactone - trans-(+/- )-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-di-diphenyl-1-[2-(tetrahydro-4- hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide. 
This racemate was divided by chiral synthesis which was made analogously the method in US Pat. No. 4,581,893. Then each isomer was saponificated with NaOH and purificated by HPLC. 
The calcium salt corresponding acid was prepared by reaction with 1 eq. of CaCl2·2H2O in water

-Mechanism of action-
As with other statins, atorvastatin is a competitive inhibitor of HMG-CoA reductase. 
Unlike most others, however, it is a completely synthetic compound. 
HMG-CoA reductase catalyzes the reduction of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate, which is the rate-limiting step in hepatic cholesterol biosynthesis. 
Inhibition of the enzyme decreases de novo cholesterol synthesis, increasing expression of low-density lipoprotein receptors (LDL receptors) on hepatocytes. 
This increases LDL uptake by the hepatocytes, decreasing the amount of LDL-cholesterol in the blood. 
Like other statins, atorvastatin also reduces blood levels of triglycerides and slightly increases levels of HDL-cholesterol.

In people with acute coronary syndrome, high-dose atorvastatin treatment may play a plaque-stabilizing role. 
At high doses, statins have anti-inflammatory effects, incite reduction of the necrotic plaque core, and improve endothelial function, leading to plaque stabilization and, sometimes, plaque regression. 
There is a similar thought process with using high-dose statins to prevent recurrence of thrombotic stroke.

-Medical uses-
The primary uses of atorvastatin is for the treatment of dyslipidemia and the prevention of cardiovascular disease:

Dyslipidemia:
Hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Fredrickson types IIa and IIb) to reduce total cholesterol, LDL-C, apo-B, triglycerides levels, and CRP as well as increase HDL levels.

Heterozygous familial hypercholesterolemia in children

Homozygous familial hypercholesterolemia

Hypertriglyceridemia (Fredrickson Type IV)

Primary dysbetalipoproteinemia (Fredrickson Type III)

Combined hyperlipidemia

Cardiovascular disease:
Primary prevention of heart attack, stroke, and need for revascularization procedures in people who have risk factors such as age, smoking, high blood pressure, low HDL-C, and a family history of early heart disease, but have not yet developed evidence of coronary artery disease.

Secondary prevention of myocardial infarction, stroke, unstable angina, and revascularization in people with established coronary artery disease.

Myocardial infarction and stroke prevention in people with type II diabetes.
A 2014 meta-analysis showed high-dose statin therapy was significantly superior compared to moderate or low-intensity statin therapy in reducing plaque volume in patients with acute coronary syndrome. 
The SATURN trial which compared the effects of high-dose atorvastatin and rosuvastatin also confirmed these findings. Despite the high dosage, the 40 mg pravastatin study arm in the REVERSAL trial failed to halt plaque progression, which suggests other factors such as which statin is used, duration and location of the plaque may also affect plaque volume reduction and thereby plaque-stabilization. 
Overall, plaque reduction should be considered as a surrogate endpoint and should not be directly used to determine clinical benefit of therapy.Increased risk of adverse events should also be taken into account when considering high-dose statin therapy.

Kidney disease:
In people with cardiovascular disease, statins including atorvastatin, do not reduce the risk of kidney failure, but have shown to modestly reduce the progressive decline in kidney function and the severity of protein excretion in urine. Statins, including atorvastatin, before heart surgery do not prevent acute kidney injury.

Prior to contrast medium (CM) administration, pre-treatment with atorvastatin therapy can reduce the risk of contrast-induced acute kidney injury (CI-AKI) in patients with pre-existing chronic kidney disease (CKD) (eGFR < 60mL/min/1.73m2) who undergo interventional procedures such as cardiac catheterisation, coronary angiography (CAG) or percutaneous coronary intervention (PCI). A meta-analysis of 21 RCTs confirmed that high dose (80 mg) atorvastatin therapy is more effective than regular dose or low dose statin therapy at preventing CI-AKI. Atorvastatin therapy can also help to prevent in-hospital dialysis post CM administration, however there is no evidence that it reduces all-cause mortality associated with CI-AKI. Overall, the evidence concludes that statin therapy, irrespective of the dose, is still more effective than no treatment or placebo at reducing the risk of CI-AKI.

-Administration-
Atorvastatin may be used in combination with bile acid sequestrants and ezetimibe to increase reduction in cholesterol levels. Statins may also be used in combination with fibrates to manage dyslipidaemia in type 2 diabetes mellitus patients, who are at a high risk of cardiovascular disease. However, it is recommended to avoid its use with gemfibrozil due to glucuronidation of statin, which may increase the risk of rhabdomyolysis.

While many statin medications should be administered at bedtime for optimal effect, atorvastatin can be dosed at any time of day, as long as it is continually dosed once daily at the same time.

Specific populations:
Geriatric: Plasma concentrations of atorvastatin in healthy elderly subjects are higher than those in young adults, and clinical data suggests a greater degree of LDL-lowering at any dose for people in the population as compared to young adults.

Pediatric: Pharmacokinetic data is not available for this population.

Gender: Plasma concentrations are generally higher in women than in men, but there is no clinically significant difference in the extent of LDL reduction between men and women.

Kidney impairment: Kidney disease has no influence on plasma concentrations of atorvastatin and dosing need not be adjusted in these people.

Hemodialysis: There has been moderate-to-high quality of evidence to show the lack of clear and significant clinical benefits of statins, including atorvastatin, in minimizing non-fatal myocardial infarction, stroke, and cardiovascular mortality in adult patients on haemodialysis  (including those with diabetes and/or pre-existing cardiovascular diseases) despite the clinically-relevant reduction in total/LDL cholesterol levels. However, a post hoc analysis on atorvastatin had revealed that it may still be beneficial  in reducing combined cardiac events, cardiac and all-cause mortality in those with a higher baseline LDL cholesterol >3.75 mmol/L. While the SHARP study suggested that LDL cholesterol-lowering treatments (e.g. statin/ezetimib. combination) are effective in reducing the risks of major atherosclerotic events in the CKD patients including those on dialysis, the subgroup analysis of the haemodialysis patients had revealed no significant benefits. Whether or not haemodialysis had any impact on the statin levels was not specifically addressed in these major trials.

Hepatic impairment: In people with chronic alcoholic liver disease, levels of atorvastatin may be significantly increased depending upon the extent of liver disease.

-General Description-
Atorvastatin,[R-(R*,R*)]-2-(4-fluorophenyl)-b,d-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-1-heptanoic acid(Lipitor), also possesses the heptanoic acid side chain,which is critical for inhibition of HMG-CoA reductase.Although the side chain is less lipophilic than the lactoneform, the high amount of lipophilic substitution causes this agent to have a slightly higher level of CNS penetration thanpravastatin, resulting in a slight increase in CNS side effects.Even so, its CNS profile is much lower than that of lovastatin.Atorvastatin is marketed as a combination therapywith amlodipine under the trade name Norvasc for managementof high cholesterol and high blood pressure.

Cerivastatin (Baycol) is one of the neweragents in this class of cholesterol-lowering agents. However,it carries a higher incidence of rhabdomyolysis and, as a result,was voluntarily withdrawn from the market by its manufacturerin 2001.

-Synonyms-
atorvastatin
134523-00-5
Cardyl
Lipitor
ATORVASTATIN CALCIUM
Torvast
UNII-A0JWA85V8F
(3R,5R)-7-(2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoic acid
110862-48-1
CI 981
Lipitor (TN)
Tozalip
Xavator
A0JWA85V8F
CHEMBL1487
(3R,5R)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid
(R-(R*,R*))-2-(4-Fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-((phenylamino)carbonyl)-1H-pyrrole-1-heptanoic acid
CHEBI:39548
(3R,5R)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-(propan-2-yl)-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoic acid
134523-03-8
Atorvastatin [INN:BAN]
1H-Pyrrole-1-heptanoic acid, 2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-((phenylamino)carbonyl)-, (R-(R*,R*))-
7-[2-(4-FLUORO-PHENYL)-5-ISOPROPYL-3-PHENYL-4-PHENYLCARBAMOYL-PYRROL-1-YL]- 3,5-DIHYDROXY-HEPTANOIC ACID
Atoevastatin calcium salt
atorvastatina
atorvastatine
atrovastin
Atofast
Atorcor
Atorlip
Lipilou
Lipinon
Atorin
Ator
Lipitor(TM)
(3R,5R)-7-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoic acid
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
(3R,5R)-7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoic acid
Atorvastatin (INN)
Sortis (TN)
CCRIS 7159
MFCD00899261
C33H35FN2O5
HSDB 7039
NCGC00159458-03
atorvastatinum
rel-Atorvastatin
(betaR,deltaR)-2-(p-Fluorophenyl)-beta,delta-dihydroxy-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)pyrrole-1-heptanoic acid
Atorvastatin & Primycin
DSSTox_CID_9868
SCHEMBL3831
DSSTox_RID_78825
DSSTox_GSID_29868
BIDD:GT0336
Atorvastatin (Relative Stereo)
GTPL2949
DTXSID8029868
BDBM22164
DTXSID60274003
HMS3715L05
HMS3886C20
Lipilou; Tozalip; Torvast; Cardyl
ACT03225
HY-B0589
ZINC3920719
Tox21_302417
s5715
AKOS000281127
AC-9386
CCG-221172
DB01076
MCULE-2368532812
MRF-0000761
NCGC00159458-02
NCGC00159458-20
NCGC00255181-01
(3R,5R)-7-[2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid
1H-Pyrrole-1-heptanoic acid, 2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-((phenylamino)carbonyl)-, (betaR,deltaR)-
7-[2-(4-FLUORO-PHENYL)-5-ISOPROPYL-3-PHENYL-4-PHENYLCARBAMOYL-PYRROL-1-YL]-3,5-DIHYDROXY-HEPTANOIC ACID
AS-35260
H942
CAS-134523-00-5
C06834
D07474
523A005
A802259
A806791
A806793
Q668093
SR-01000872702
SR-01000872702-1
BRD-K69726342-001-02-6
UNII-36TN91XZ0V component XUKUURHRXDUEBC-KAYWLYCHSA-N
(3R,5R)-7-[2-(4-FLUOROPHENYL)-3-PHENYL-4-(PHENYLCARBAMOYL)-5-PROPAN-2-YL-PYRROL-1-YL]-3,5-DIHYDROXY-HEPTANOIC ACID
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
(3R,5R)-7-[3-(anilinocarbonyl)-5-(4-fluorophenyl)-4-phenyl-2-(propan-2-yl)-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoic acid
1H-Pyrrole-1-heptanoic acid, 2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-((phenylamino)carbonyl)-, (beta-R,delta-R)-;
sodium 7-[5-(4-fluorophenyl)-2-isopropyl-4-phenyl-3-(phenylcarbamoyl)-2,3-dihydropyrrol-1-yl]-3,5-dihydroxy-heptanoateo