Talking about the development of Me-too drugs through case analysis

For example, Polite (Rabeprazole sodium) was launched in Japan in 1998, and it was introduced to Europe in 1999.
In the same year, it was approved by the US FDA for listing in the United States.
It brought brand-new treatment options and gained a lot of foreign countries in a short time.
Doctor’s approval, for many patients with peptic ulcer and gastroesophageal reflux disease, it can be seen from the structural comparison that it is a structural analogue of omeprazole, its structure is very similar to lansoprazole, but the side chain is slightly changed , The original trifluoroethoxy group was replaced with methoxypropoxy group, and the other parts are basically the same, which also belongs to a kind of "Me-too medicine"
.

Tenatoprazole, which was launched in Japan in 2004, is a new type of gastric H+/K+-ATPase inhibitor jointly developed by Tanabe, Japan, Mitsubishi Corporation, and Hokuriku Pharmaceutical Co.
, Ltd.
(Proton Pump Inhibitor) Agent)
.
The drug significantly inhibits the secretion of gastric acid and also has an inhibitory effect on Helicobacter pylori
.
The curative effect is 7 times stronger than omeprazole, and the stability is also significantly improved compared with omeprazole
.
In terms of its structure, the benzene ring in the omeprazole structure is replaced with a pyridine ring to produce another new drug
.

Me-too study of dihydropyridine calcium antagonists

Dihydropyridine calcium antagonists are a class of drugs with high specificity and strong action.
They have strong vasodilator effects and are suitable for coronary artery spasm, hypertension, and myocardial infarction
.

Nifedipine was the first to be used.
People synthesized a series of "dipine" compounds based on the structural modification of the structure-activity relationship: Aranidipine was listed in 1996 by the Japanese company Taiho.
New dihydropyridine drugs
.
It is modified on the basis of nifedipine by replacing the methyl hydrogen on the 3-position of the dihydropyridine ring with an acetyl group
.
The drug can stereoselectively inhibit calcium channels, and the rate of binding and dissociation with the receptor is slower, and the antihypertensive effect is longer than nifedipine
.

Cinildipine (Cinildipine) is a long-acting dihydropyridine calcium antagonist marketed by Japan Fuji Co.
, Ltd.
in 1996.
It is obtained by replacing the ester group at the 3 and 5 positions of nifedipine.
The type double bond has an obstructive effect on calcium channels and is also a long-acting antihypertensive drug
.
The latter two drugs are new drugs based on the structure of nifedipine, and they are both classic representatives of Me-too drugs
.

Me-too study of hydroxymethylglutaryl-CoA reductase inhibitor

In the early 1970s, several microbiologists such as Endo of Kitasato Medical Research Institute in Japan discovered by chance that an unknown substance can inhibit the activity of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase, thereby Significantly lower the cholesterol in the plasma
.
Japanese scientists named this newly discovered substance compactin (Mevastatin)
.

The discovery of mevastatin opened a new era in the search and development of HMG-CoA reductase inhibitors to regulate blood lipids
.
However, because the industrialization technology at that time did not completely pass the customs, and the Japanese pharmaceutical companies did not invest the NPC funds to continue the in-depth development of mevastatin and other derivative products, and ultimately failed to form production capacity, and lost statins to regulate blood lipids.
Advantages of drug development
.

However, the research results of Japanese scholars on statin lipid drugs have aroused strong interest among colleagues in the medical field of western countries
.
The United States, Germany, Britain, France, Switzerland and other established pharmaceutical industry powers have invested a lot of manpower and financial resources in the research and development of statins, and have achieved fruitful results
.

In less than 20 years, Western countries have developed a total of more than 10 statins, including mevastatin, to regulate blood lipids
.
Lovastatin, developed by Merck, was first marketed in the United States in 1987 and became the first statin to be marketed.
It is an inactive prodrug that requires the ester ring to be hydrolyzed into an open chain hydroxy acid in the body.
Derivatives have anti-enzyme activity.
The drug can competitively inhibit HMG-CoA reductase, reduce cholesterol synthesis and apolipoprotein concentration; increase the activity of low-density lipoprotein receptors; and reduce plasma triglycerides by a small amount And the concentration of cholesterol in very low-density lipoprotein, increase the level of cholesterol in serum high-density; it has a good synergistic effect when combined with lipid-lowering drugs
.

After lovastatin, it successfully developed Simvastatin (Simvastain), which is a methylated derivative of lovastatin, which is twice as active as lovastatin.
Merck applied in Europe in 1981 and the United States in 1984.
Patents
.

Subsequently, a series of Me-too drugs were produced, such as pravastatin developed by Sankyo, Switzerland, fluvastatin developed by Swiss Sandoz, cerivastatin developed by German Bayer, and Warner-Lambert (now merged) Entered Pfizer) to develop atorvastatin and so on
.

Me-too Study of Nitrogen Mustards in Bioalkylating Agents

The discovery of nitrogen mustards originated from mustard gas
.
Mustard gas is an alkylating agent poison.
It was used as a poison gas during World War I.
Later, it was discovered that mustard gas has a therapeutic effect on lymphoma
.
Because it is too toxic for medicinal use, nitrogen mustard anti-tumor drugs have been developed on this basis, so the replacement of S atoms with N atoms has become the focus of the transformation of nitrogen mustard drugs
.

From the structure of nitrogen mustards, R is the carrier part, which can improve the absorption, distribution, and other pharmacokinetic properties of this type of drug in the body.
The other part is the functional group of anti-tumor activity when the alkylation part is used
.
When the carrier part is an aliphatic hydrocarbon group, it becomes aliphatic nitrogen mustard, and when it is substituted by an aromatic ring, it becomes an aromatic nitrogen mustard
.

Studies on the structure-activity relationship of aromatic nitrogen mustards show that when the number of atoms between the carbon atoms between the carboxyl group and the benzene ring is 3, the effect is best, that is, chlorambucil (Chlorambucil), which is used for the treatment of chronic lymphocytic leukemia , It also has a good effect on lymphosarcoma, Hodgkin’s disease and ovarian cancer.
Its sodium salt is clinically used, which has good water solubility and is absorbed by the gastrointestinal tract.
It is quickly converted into free chlorambucil in the body
.

Another successful example is the substitution of aromatic acids on the side chains and the introduction of naturally-occurring amino acids in order to increase the concentration and affinity of the drug at the tumor site and improve the efficacy of the drug
.
For example, Melphalan (sarcolysin), which uses phenylalanine as a carrier, has a good curative effect on malignant tumors such as ovarian cancer, breast cancer, lymphosarcoma and multiple bone marrow
.

Chinese scholars have formylated NH2 on the basis of melphalan to obtain Formylmerphalan.
Compared with sarcolysin, it has a higher therapeutic index and lower toxicity
.

In the reality of China's increasingly perfect patent system, relatively insufficient investment in research and development of new drugs, and relatively backward research levels
.
Using the Me-too strategy to discover new drugs, compared with new drug innovation, reduces the technical difficulty, risk and R&D cost, which can avoid patent infringement and speed up the research of chemically synthesized drugs in China
.
Provide the necessary technology accumulation and capital accumulation for the research and development of new drugs, and promote the development of China's pharmaceutical industry
.

Reference materials:

You Qidong.
Medicinal Chemistry

Wang Shuyue, Wang Hongliang.
On the status of Me-too drugs in the research of new drugs

Liu Ruiwu.
Tailor-made Me-too new medicine