From snake venom to antihypertensive drug, the path to discovery of the classic drug Cattoply.

Text . . . Captopril is the first listed angiotensin-converting enzyme inhibitor (angiotensin-enzymeing inhibitors, ACEI).
the legendary development of the drug, not only proved the important role of ACE in hypertension, but also one of the models of drug design, and provided a blueprint for the subsequent development of ACEI drug. the analysis of the effects of the
01RAAS system on hypertension in humans on angiotensin-converting enzyme (angiotensin-converting enzyme, ACE) is considered to be an important breakthrough in hypertension treatment.
this finding is based primarily on understanding the renin-angiotensin-aldosterone system in the kidneys of the body.
RASS is a boost regulation system produced by the kidneys, a protein hydrolysis enzyme secreted by the near-sphere cells of the kidneys, produced by response to a drop in blood pressure or a drop in the concentration of Na plus in the blood.
on the one hand, the secretion of renin to the angiotensin to lysing into angiotensin I, the substance on blood pressure rise and fall without any activity.
ACE can convert angiotensin I into active angiotensin II.
angiotensin II has many physiological effects, the substance increases vascular resistance, acts on the adrenal cortex to release aldehyde ketones, enhances the reabsorption of Na plus.
At the same time, angiotensin II also activates its receptors as an agonisant, causing a series of corresponding physiological changes, which eventually lead to tightness of the blood vessel walls and elevated blood pressure.
in addition, vascular peptides themselves have the effect of promoting blood vessel dilation and lowering blood pressure.
RAAS system regulates blood pressure mechanism angiotensin-enzyme inhibitor enzymes (angiotensin-converting enzymes, ACEI) by inhibiting ACE activity, thereby inhibiting angiotensin I into angiotensin II, reducing the production of angiotensin II, and inhibiting the degradation of retardant peptides, thus having the effect of diastolic blood vessels and lowering blood pressure.
Catopuri (commodity name Captopril) is the first generation of oral ACEI, which originally originated from the Brazilian snake venom in a slow-motion peptide, can effectively treat a variety of primary hypertension, with rapid effect, smooth blood pressure, long-term efficacy and other advantages, while heart failure and diabetes, kidney disease also has a good therapeutic effect.
's advent of Catopuri ushered in a new era of high blood pressure medication.
today, the research of ACEI, represented by Catopuri, is still one of the hot topics in drug chemistry research.
the secret of the snake venom in the history of The Discovery of Captoply dating back to 1933, when Rochae Silva discovered that patients bitten by a Brazilian python had hypotension symptoms, leading to speculation that snake venom might contain a "blood pressure-lowering substance."
Until 1948, Rochae Silva extracted a "blood pressure-lowering substance" from the snake venom of a python in Brazil and proved that the substance was a straight-chain nine-peptide compound named "slow-stimulating peptide".
senocin can only be stable in snake venom, the half-life in the human body is very short, only a few minutes will be completely decomposed.
, the researchers speculated that a substance that could stabilize the peptides may exist in the snake.
In the 1960s, John R. Vane worked on the causes of hypertension.
Vane is a legendary figure who won the 1982 Nobel Prize in Medicine for his work on aspirin.
Vane also rose to fame by researching antihypertensive drugs.
In 1965, a Brazilian postdoctoral student, Sergio Ferreira, obtained a slow-kinin pyreth (Bradykinin heting factor, BPF) extract in brazilian python venom, and Ferreira also confirmed that BPF can enhance the action of peptides by inhibiting the peptide degradation enzyme. After
, BPF was tested for angiotensin conversion enzyme (ACE) and found to be an effective inhibitor.
this has led to Vane's interest in ACE and its inhibitory effect as a means of treating hypertension.
Ferreira et al. first discovered a peptide called BPP5a, which has a good antihypertensive effect, but the compound has a very short half-life in humans. After
, researchers found six other peptides, and after experimental tests, a nine-peptide called teprotide was favored by researchers, with a long half-life and excellent bucking effect.
Teprotide's chemical structure (Source: Reference 1) 03 Key Theory at the time, Vane was a professor of pharmacology at the Royal College of Surgeons, and he was also E.R. Consultant to Squibband Sons Pharmaceuticals, one of the predecessors of Baxter.
And Charles G. Smith is squibb's head of research and development.
Vane introduced the concept of ACE as the primary regulator of blood pressure to Squibb, however, the prevailing view at the time was that ACE played a role in so-called "malignant hypertension" (a rapidly elevated blood pressure and a serious threat to life).
ACEI is not valued commercially because it accounts for only 5% of hypertension and has drugs for the condition.
Vane, through the study of hypertension, believes that the ACE system may play an important role in "primary hypertension".
he eventually convinced squibb's researchers.
because the company has not yet produced competitive antihypertensive drugs, if Vane's theory is correct, it will give the company a chance to "jump" into the cardiovascular field."
04 Cattoply's discovery, however, Vane et al.'s experiment was to study polypeptides in snake venom in vitro.
and peptides must be injected to be effective in the body.
and injection is not the best way to treat hypertension.
and Squibb's researchers synthesized more than 2,000 compounds without exception.
at a time when the mountains were running out, the researchers found that the biochemical mechanism of ACE was similar to that of peptide asse A.
and the structure of peptide aselase A has been characterized, but it was not until 2003 that the structure of ACE was known, so at that time researchers used the known pyrethyth aphine A structure to guide the development of ACEI.
the schematic a structure diagram of the peptide enzyme (Source: Reference 7) the peptide asse A contains Zn2 plus, and Zn2 plus plays an important role in the activity of peptide asse A.
L-carnitine succinic acid has an inhibitory effect on pyridine a, and two argon sepse in L-carnitine sepse binds to Zn2 plus in argon-based sepse a, resulting in inhibitory activity.
the graph of L-carine succinic succinic acid and Zn2 plus binding in pyrethalynase A (Source: Reference 6) The researchers were inspired to creatively combine teprotide with the structure of L-carat succinic succinic acid to synthesize a series of compounds (shown below).
the creative move to get creative structures (Source: Reference 1) brought unexpected surprises to the entire project, with IC50 values of compounds 7 and 10 of 330 ?M and 70 ?M, respectively, bringing a glimmer of light to the success of the project, and continuing to optimize these compounds to get the structure shown in the figure below.
introduce methyl as a replacement base at different positions in the methyl chain between the molybdenum and the argon base of the compound, and determine the activity of each compound.
concluded that the activity of methyl in beta was higher than that of alpha, and that the activity of R-type compounds was higher than that of S-type compounds and exoskeleton mixtures.
optimized structure (Source: Reference 1) Although the activity of methyl substitution compounds has increased significantly, it still falls short of the standard of a pharmaceutical.
the researchers started from the active site of the binding of pyridoxelase A and inhibitor, the active site of the protein is Zn2 plus, if the synthesis of a stronger compound with the binding force of Zn2 plus, will produce a stronger inhibitory effect.
the researchers replaced the argon base with a pyridine base, which can form a metal chelate with a stronger binding force (as shown in the figure below).
optimized structure (source: reference 1) sure enough, the emperor does not bear the heart, get compound 21 IC50 reached the nM grade inhibition effect, has a good medicinal properties, which is later the antihypertensive drug catoply.
the rough clinical trials of 05 were not easy in the 1970s, when most clinical experts in the field did not believe that ACE played an important role in primary hypertension.
Smith invited dozens of clinical experts to ask if they would like to study a drug that suppresses ACE, but unfortunately most declined and only two expressed interest.
John Laragh, a professor at Columbia University's school of medicine at the time, offered to give it a try.
when Squibb applied to the FDA for a clinical trial, the application was rejected because it did not meet FDA requirements.
Squibb was undeterred, conducting its first clinical trial in the UK with Vane's support.
tests in the UK have proven the effectiveness of the drug, and the FDA has approved an aceI clinical trial in patients with primary hypertension.
06 successfully listed due to the good results of Catopuri, successfully completed clinical trials, the United States FDA approved The Sale of Captopri in June 1981.
has since been approved for the market of a variety of ACEI drugs, such as Inapree, Renopri and so on.
in 1988, ACEI's sales reached $780 million; in 1992, Capuply had more than $1.6 billion; and in 1992, the rising star of Inapri had more sales than Capuply because of the severity of the side effects.
the patent expired in 1996, so the price of captopril has plummeted since then, and hundreds of domestic drug companies are producing the drug.
Catopi was Squibb's first bombshell, opening up new avenues for treating high blood pressure.
the success of Catopuri not only proved the correctness of the ACE concept, but also a model of rational design of drugs, which provided ideas for the subsequent research and development of ACEI.
References: 1. Angioin-Converting Enzyme Seins for The Treatment of The S. The Discovery of Captopril.3. Historyof the Design of Captopril and Related Sofs of Angiotensin Converting Enzyme.4. From snake snake venom to ACE - the discovery and rise of captopril.5. The discovery of captopril: from large animals to small molecules.6. Binding of the Biproduct Analog L-Benzylsuccinic Acid to Thermolysin DYby X-ray Crystallography.7.