Captopril is an angiotensin converting enzyme inhibitor (ACE inhibitor or ACEI), which is used to treat hypertension and certain types of congestive heart failure. As the first ACEI drug to be marketed, due to its new mechanism of action and revolutionary development process, captopril is considered to be a breakthrough in drug therapy, and this not only proves the important role of ACE on hypertension, It has also become one of the models of drug design and provided a blueprint for the subsequent development of ACEI drugs.

The secret of snake venom-bradykinin was discovered

Captopril is the first generation of oral ACEI, which was originally derived from a bradykinin in Brazilian snake venom. The only discovery can be traced back to 1933 when Mauricio Rocha, a medical intern at the University of São Paulo e Silva, 1910-1983) found that patients bitten by a Brazilian viper would have symptoms of hypotension. It is therefore speculated that snake venom may contain "hypertensive substances".

It was not until 1948 that Rochae Silva extracted a "hypertensive substance" from the snake venom of the Brazilian Agkistrodon, and proved that the substance was a linear nonapeptide compound named "bradykinin". Bradykinin can only exist stably in snake venom, and its half-life in the human body is extremely short, and it will be completely decomposed in just a few minutes. Therefore, researchers speculate that there may be a substance that stabilizes bradykinin in venomous snakes.

In the 1960s, John R. Vane devoted himself to studying the causes of hypertension. Vane is a legend and won the 1982 Nobel Prize in Medicine for his research on aspirin. Vane also gained fame through research on antihypertensive drugs.

In 1965, a Brazilian postdoctoral fellow Sergio Ferreira obtained a bradykinin potentiating factor (BPF) extract from the Brazilian viper venom. Ferreira also confirmed that BPF can enhance bradykinin by inhibiting bradykinin degrading enzymes. The role of.

Afterwards, BPF was tested for angiotensin converting enzyme (ACE) and found to be an effective inhibitor. This aroused Vane's keen interest in ACE and its inhibitory effect as a means of treating hypertension.

Erreira et al. first discovered a polypeptide called BPP5a, which has a good hypotensive effect, but the compound has an extremely short half-life in the human body. Later, many researchers discovered six other peptides. After experimental tests, a nonapeptide called teprotide was favored by researchers. This compound has a long half-life and excellent antihypertensive effect.

At that time, Vane was a professor of pharmacology at the Royal College of Surgeons in the United Kingdom. In addition, he was also a consultant for E.R. Squibband Sons Pharmaceuticals (one of the predecessors of Bristol-Myers Squibb). And Charles G. Smith is the head of research and development at Squibb. Vane introduced the concept of ACE as a major blood pressure regulator to Squibb. However, the mainstream view at the time believed that ACE played a role in so-called "malignant hypertension" (a rapid increase in blood pressure and a serious threat to life). Because this situation only accounts for 5% of hypertension and there are drugs suitable for this symptom, ACEI is not taken seriously in business.

Through research on hypertension, Vane believes that the ACE system may play an important role in "essential hypertension". He eventually convinced the Squibb researchers. Since the company has not yet produced competitive antihypertensive drugs, if Vane's theory is correct, it will give the company a chance to "leapfrog" into the cardiovascular field.

However, the experiment of Vane et al. studied the polypeptides in snake venom in vitro. The peptide must be injected to be effective in the body. And injection is not the optimal route of administration for the treatment of hypertension. And Squibb researchers synthesized more than 2,000 compounds but all failed.

When the mountains are exhausted, the researchers discovered that the biochemical mechanism of ACE is similar to that of carboxypeptidase A. And the structure of carboxypeptidase A has been characterized, but people did not know the structure of ACE until 2003, so at that time researchers used the known structure of carboxypeptidase A to guide the development of ACEI.

Carboxypeptidase A contains Zn2+, and Zn2+ plays an important role in the activity of carboxypeptidase A. L-benzyl succinic acid has an inhibitory effect on carboxypeptidase A. The two carboxyl groups in L-benzyl succinic acid bind to Zn2+ in carboxypeptidase A, thereby producing inhibitory activity.

The discovery of captopril

The researchers were inspired by this and creatively combined the structure of teprotide and L-benzyl succinic acid to synthesize a series of compounds.

This creative move brought unexpected surprises to the entire project. The IC50 values of compounds 7 and 10 were 330 μM and 70 μM, respectively, which brought a glimmer of light to the success of the project. Continue to optimize these compounds to obtain the following figure The structure shown. A methyl group was introduced as a substituent at a different position on the methylene chain between the carbonyl group and the carboxyl group of the compound, and the activity of each compound was measured. The conclusion obtained is that the activity of the methyl group at the β-position is higher than the activity at the α-position, and the activity of the compound of the R configuration is higher than that of the compound of the S configuration and the racemic mixture.

Although the activity of methyl-substituted compounds is greatly improved, they still fall short of the standards for making medicines. The researchers started from the active site where carboxypeptidase A binds to the inhibitor. There is Zn2+ on the active site of the protein. If a stronger compound that can bind to Zn2+ is synthesized, it will have a stronger inhibitory effect. The researchers replaced the carboxyl group with a sulfhydryl group, and the sulfhydryl Zn2+ can form a metal chelate with stronger binding force.

Sure enough, Huang Tian paid his attention. The IC50 of compound 21 reached the nM level of inhibition, and it has good druggability. This is also the later antihypertensive drug captopril.

Captopril's bumpy clinical trial and successfully listed

In the 1970s, it was not easy to carry out ACEI clinical trials, because most clinical experts in the field did not believe that ACE played an important role in essential hypertension. Bristol-Myers Bristol-Myers Squibb invited dozens of clinical experts to ask if they would like to study a drug that can inhibit ACE. Unfortunately, most people refused, but only two expressed interest. John Laragh, a professor at the Columbia University School of Medicine at the time, expressed his willingness to give it a try.

When Squibb applied to the US FDA for a clinical trial, the application was rejected because it did not meet FDA requirements. Squibb was not discouraged and, with the support of Professor Fann, conducted its first clinical trial in the UK. The test in the UK verified the effectiveness of the drug, so the US FDA made an exception and agreed to a clinical trial of ACEI for the treatment of patients with essential hypertension. Due to the good effects of captopril, the US FDA approved captopril for marketing in June 1981. Since then, captopril has been approved for use in diseases such as heart failure and diabetic nephropathy, which has brought good news to several patients around the world.

However, a key sulfhydryl group gave captopril a highly effective inhibition of angiotensin converting enzyme, which enabled Bristol-Myers Squibb to seize the opportunity for research and development. However, sulfhydryl group also brought captopril side effects, such as skin rash. , Dysgeusia, dry cough, etc., which leaves room for improvement in the subsequent research and development of other pharmaceutical companies.

Captopril opened up a new way for the treatment of hypertension. Its success not only proved the correctness of the ACE concept, but was also a model of rational drug design, and provided ideas for the subsequent development of ACEI.