The latecomers are on top: the growth path of atorvastatin

To understand atorvastatin, we first need to understand the history of cholesterol discovery
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In 1816, Frenchman Cherzeul took the lead in naming a lipid-like substance found in gallstones as cholesterol
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In 1841, Russian Vogel confirmed the presence of cholesterol in atherosclerotic plaques on arterial walls
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But at this time, people still don't know that cholesterol is the culprit that causes atherosclerosis in the arterial walls
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In 1910, German Adolf Windaus, known as the "father of steroids," was the first to discover that atherosclerosis was associated with abnormally elevated cholesterol when studying cholesterol in human autopsy specimens
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In 1913, the Russian pathologist Anitschkow succeeded in establishing the world’s first animal model of atherosclerosis by feeding rabbits a high-cholesterol diet, which also indirectly proved Adolf Wendaus.
Discovery
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Atherosclerosis (AS) is the main cause of coronary heart disease, cerebral infarction, and peripheral vascular disease
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Lipid metabolism disorder is the pathological basis of atherosclerosis
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How does the synthesis and metabolism of cholesterol proceed? The research on the metabolism and synthesis of cholesterol has won the Nobel Prize
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In 1974, American scientists Goldstein and Brown used the skin fibroblasts of patients with homozygous FH (familial hypercholesterolemia) as the object, and discovered that there is a high-affinity LDL (low-density lipoprotein, a form of cholesterol) on the cell membrane surface.
) Receptor
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They also won the 1985 Nobel Prize in Physiology or Medicine for discovering the mechanism of cholesterol metabolism
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In 1942, Bloch successfully discovered the entire process of cholesterol biochemical synthesis
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This is a complex system with more than 30 steps of enzyme-catalyzed reaction starting from a raw material called "acetyl-CoA"
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The process is going on in the liver, and its sophistication and complexity is simply dazzling! In the end, Bloch shared the 1964 Nobel Prize in Physiology or Medicine with the German scientist Feodor Lynen who discovered acetyl-CoA, the raw material for cholesterol synthesis
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When conducting drug development, scientists are looking for targets in the cholesterol production pathway
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In 1959, the Max-Planck Institute first discovered HMG-CoA reductase; in the 1960s, Siperstein et al.
proved that the function of HMG-CoA reductase was to catalyze the conversion of HMG-CoA to MVA, and inhibiting the activity of this enzyme would effectively reduce cholesterol.
The biosynthesis, which in turn reduces plasma cholesterol
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What we commonly call statins refers to HMG-CoA reductase inhibitors
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Hydroxymethylglutarate (HMG-CoA) is water-soluble.
When HMG-CoA reductase is inhibited, there is an alternative pathway of catabolic pathway, which will not cause accumulation toxicity
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Therefore, HMG-CoA reductase is an excellent target
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In 1971, Akira Endo, a microbiologist at Sankyo Company in Japan, discovered in the fermentation broth of Penicillium citrinum, a natural product that has a strong inhibitory effect on HMG-CoA reductase-mevastatin
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They confirmed that the structure of mevastatin consists of two parts: the hexahydronaphthalene ring skeleton and the β-hydroxy-δ-lactone.
After the lactone ring is opened, the side chain of 3,5-dihydroxyheptanoic acid is 3-methyl.
3,5-Dihydroxyvaleric acid (MVA) is a structural analogue, so mevastatin exerts an inhibitory effect by competitively blocking HMG-CoA reductase
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In 1979, Merck purified the effective inhibitor of HMG-CoA reductase from the fermentation broth of Aspergillus terreus-later named Lovastatin
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In 1982, the clinical trial was completed in the United States
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In 1987, it was approved by the FDA and became the first statin to be marketed under the trade name of Mevacor.

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As early as the mid-1980s, when lipid-lowering was not yet on the market in the United States, Merck had already begun to develop another lipid-lowering drug-simvastatin, which was later marketed in the United States under the trade name Zocor (Zocor) in early 1992 (Simvastatin) tablets
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In 1985, Bruce Roth synthesized atorvastatin calcium for the first time, which was subsequently acquired by Pfizer and named the product Lipitor
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After being artificially synthesized for the first time, atorvastatin has undergone a series of developments, including the improvement of the synthesis process, the active exploration of indications, the improvement of side effects, the expansion of the market, the birth of generic drugs, and so on
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The atorvastatin calcium in Lipitor is a compound formed by connecting two molecules of atorvastatin through Ca.
Its advantage is that the drug effect in the body is maintained for a longer time, but it still needs to be dissociated into atorvastatin to play a role.

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Therefore, the improvement of the drug synthesis path is mainly focused on the improvement of the single molecule synthesis of atorvastatin
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Since Bruce Roth, new synthetic routes of atorvastatin have been continuously developed.
There are multiple classifications based on starting materials alone: ​​including 2-(4-fluorophenyl)-2-bromo-ethyl acetate As the starting material, atorvastatin aldehyde as the starting material, phenylacetic acid as the starting material, L-valine as the starting material, etc.
, it also includes the cheap and easily available (R)-2- Chloromethyl oxirane is used as the raw material to avoid the dangerous synthetic route of Raney nickel
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In the broadening of indications, atorvastatin also performed very well
.
We know that atorvastatin was initially just a hypolipidemic drug, which can lower cholesterol in the body by reducing liver biosynthesis
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But in addition to the lipid-lowering function, atorvastatin also inhibits the proliferation and migration of vascular smooth muscle and promotes its apoptosis.
It can improve the patient's blood rheology and blood viscosity, thereby improving heart function, vascular endothelial function and blood coagulation.
Function, clinically can also be used to prevent coronary heart disease and heart failure and other diseases, the effect can be described as extensive
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In recent years, studies have pointed out that atorvastatin can inhibit the proliferation of tumor cells, promote the differentiation and apoptosis of tumor cells, affect cell cycle and molecular signal transduction, etc.
, and its adverse reactions are smaller than conventional chemotherapy drugs.
Vastatin is used in the treatment of tumors
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Taking the p53 gene as an example, a review on Nature Review Cancer in 2016 introduced in detail that a signaling pathway controlled by the p53 gene, the mevalonate pathway (MVP), perfectly overlaps with the statin lipid-lowering pathway
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Wild-type p53 gene can inhibit the occurrence of liver cancer at an early stage.
During the initiation of this tumor suppressor program, MVP is strictly controlled by p53
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Mutations in the p53 gene can up-regulate MVP, thereby increasing the invasiveness of cancer cells
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The MVP pathway is not only an important downstream pathway of the p53 gene, but also an important source of precursors for cholesterol synthesis in the body
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Studies have shown that while statins inhibit MVP and lower cholesterol levels, they can also inhibit the up-regulation of MVP by p53 mutants, thereby inhibiting cancer cell invasiveness
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Before discussing the pharmacology of atorvastatin, it is necessary to explain the research background: the conversion and accumulation of cholesterol in the process of fat transport
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Background studies have shown that low-density lipoprotein (LDL) is the primary culprit that causes cholesterol to accumulate on the blood vessel walls, leading to cardiovascular disease
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In contrast, high-density lipoprotein (HDL) can remove cholesterol from blood vessel walls and transport it to the liver for absorption
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It can be seen from the background that inhibiting the production of LDL cholesterol can reduce blood lipids, thereby reducing the risk of cardiovascular disease
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Studies have shown that HMG-CoA reductase is the rate-limiting enzyme in cholesterol biosynthesis (the catalytic enzyme for the rate-determining step in multi-step biochemical reactions)
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In this step, HMG-CoA reductase catalyzes the conversion of HMG-CoA into MVA (3-methyl-3,5-dihydroxyvaleric acid)
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The mechanism of action of statins is closely related to this reaction
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The 3,5-dihydroxy acid side chain of statins can bind to HMG-CoA reductase and inhibit the binding of HMG-CoA reductase to HMG-CoA, thereby inhibiting the synthesis of cholesterol
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The orientation and bonding interaction of the 3,5-dihydroxy acid side chain part of statins are very similar to the binding effect of HMG-CoA
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A large number of hydrogen bonding and the existence of ion pairs lead to the complementary charge and shape between the protein and the side chain part of the statin 3,5-dihydroxy acid, resulting in a strong binding ability
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When combined with enzymes, the hydrophobic ring of statins is in a narrow hydrophobic pocket
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The hydrophobic pocket of the enzyme protein and the hydrophobic ring of the statin are combined by van der Waals force
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Compared with other statin drugs, the hydrophobic group of atorvastatin has the obvious feature that the carbonyl group of its amide bond can be combined with Ser-565 site through hydrogen bond, and it also has the commonality of type 2 statin drugs: fluorobenzene The fluorine atom of Arg-590 has a strong polar interaction with the guanidine group at the Arg-590 position
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These effects enable the hydrophobic group of atorvastatin to also bind tightly to enzymes
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In addition, the pharmacokinetics of atorvastatin (ADME) has also been fully studied
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In terms of absorption, oral atorvastatin will be absorbed quickly, and it takes about 1 to 2 hours to reach the maximum plasma concentration (Tmax)
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The absolute bioavailability of the drug is approximately 14%
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In addition, when atorvastatin is taken with food or taken at night, the absorption rate will be reduced to a certain extent; in terms of distribution, the average distribution of atorvastatin is about 381L
.
It is highly bound to protein (≥98%), and studies have shown that it is likely to be secreted into human milk; metabolically, the metabolism of atorvastatin is mainly through the hydroxylation of cytochrome P450 3A4 to form active ortho and para hydroxyl groups Metabolites, and various β-oxidation metabolites
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O-hydroxy and para-hydroxy metabolites account for 70% of systemic HMG-CoA reductase activity
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O-hydroxy metabolites are further metabolized through glucuronidation; in terms of excretion, atorvastatin is mainly eliminated through hepatic bile excretion, and the recovery rate in urine is less than 2%, and no hepatic-enteric circulation is found
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The elimination half-life of atorvastatin is approximately 14 hours
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Atorvastatin is also a substrate of the intestinal P-glycoprotein efflux transporter, which pumps the drug back into the intestinal lumen during drug absorption
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When it comes to atorvastatin patents, the most influential atorvastatin product is Pfizer's Lipitor
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Lipitor can achieve proud results, efficacy and marketing are very important, but it is also inseparable from Pfizer's patented layout
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On December 7, 1996, Pfizer’s new drug application for Lipitor submitted to the FDA was formally approved; at the end of 2011, the patent for atorvastatin compounds expired, but because Pfizer had long been It has applied for a series of patents from different perspectives such as method and crystal form, and has constructed a strict patent protection network for Lipitor, so it can still extend the protection period of related products to a certain extent
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In 2011, the Lipitor compound patent expired, but its crystal form patent did not expire until 2016, becoming one of the core patents that Pfizer originally protected its products
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This multi-theme, multi-level patent protection layout effectively prolongs the protection period of its patented technology, which is worthy of reference for Chinese pharmaceutical companies
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Patent protection for drugs developed by enterprises from different angles is not only conducive to effective and adequate protection of technological achievements, but also extends the entire patent protection period of enterprises for technological achievements, and fully enjoys the exclusivity of the drug sales market during the patent protection period.
Maximize revenue
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As the world's top lipid-lowering drug, atorvastatin has achieved excellent performance since 1998
.
Lipitor (atorvastatin calcium tablets) accounted for 20% of the market share of new lipid-lowering drugs prescription drugs in the year it was launched; since 2004, sales of Famous drugs have been on the market in countries all over the world, which shows that statins have strong market vitality
.
This success is not only derived from the perfect results of the previous studies, but the later business strategy is also very important
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During the Phase III clinical trial, Warner Corporation recognized its lack of marketing capabilities, and chose to cooperate with Pfizer and was acquired by Pfizer for US$90 billion
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With Pfizer's intervention, atorvastatin has maintained good sales for many years
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In order to have a more lightning-fast market share, Pfizer also did a market research when it went public and found that its competitors had neglected a selling point of the drug: the prescription recommended by the doctor was a high-dose statin, generally between 20-40mg.
This finding Pfizer applied to the FDA for a low starting dose of Lipitor
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Before Lipitor was marketed, clinical studies had found that a dose of 10 mg had a lipid-lowering effect, so the FDA approved a dose range of 10-80 mg of Lipitor
.
This is very wise.
Doctors have seen in the approval that the highest dose of Lipitor can be used up to 80mg, so 10mg is undoubtedly safe.
This solves the doctor's long-standing concerns about the safety of statins
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At that time, Pfizer's marketing department also adjusted its pricing strategy.
Through market analysis and research on doctors and medical institutions, Lipitor's pricing was nearly half lower than that of Merck's Simvastatin
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Lipitor has the advantages of better lipid-lowering effect, more affordable price, and easier acceptance by consumers
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At the same time, Pfizer has strengthened the training of first-line medical representatives so that they can accurately grasp the market of patients and doctors
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Lipitor’s sales team took samples, visited cardiovascular doctors and family doctors many times, and grasped the advantage that the low-dose effect of Lipitor is equivalent to the high-dose effect of competing drugs, which relieved the doctor of the safety of Lipitor.
Sexual concerns
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In summary, with the support of a sound patent layout and outstanding business strategy, the success of the world's best-selling drug atorvastatin has promoted the tremendous development of lipid reduction and other various indications
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Of course, the expiration of the patents of the original research drugs has also promoted the price reduction of drugs and the rapid development of domestic research, which has promoted the rapid development of the market.

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Thanks to Mr.
Wu Xingxin for his "New Drug Research and Development Strategy" class, which brings us the knowledge about new drug research and development and the opinions of industry insiders! Thanks to our instructor, Senior Sister Wang Shenglan, for providing us with guidance and information! Thanks also to the "Yaodu" platform for providing us with a stage to show! About the author: Seeking Medicine Truth Group They are students of Nanjing University's new drug development strategy course.
This article is jointly completed by three groups of students in this course
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They are full of vigor, their fighting spirit is high, they learn new drug research and development knowledge down-to-earth, they firmly believe that I love my teacher and I love the truth more
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They are the successors of the new generation of pharmaceutical industry, and they are the light of the future in the field of new drug research and development! *This article is only for academic content exchange, and does not constitute any medication advice! References [1] Liu Hao.
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