Snake Venom and ACE Inhibitors
ACE inhibitors are drugs that inhibit the function of the angiotensin-converting enzyme (ACE). They are widely used in treating hypertension, congestive heart failure, and heart attacks. ACE inhibitors owe their genesis to snake venom—the first ACE inhibitor, teprotide, was isolated in 1971 from a poisonous venom extract of the Brazilian pit viper Bothrops jararaca.
As early as 1898, Finnish physiologist Robert Tigerstedt and his student Per Gunnar Bergman discovered that crude extracts of the kidney contained a long-acting presser substance, which they named renin. Over the next 100 years, the complex renin-angiotensin system (RAS) and its ramifications for hypertension became well elucidated. In this system, an enzyme that is involved in converting angiotensin I to angiotensin II is called angiotensin-converting enzyme, or ACE. Angiotensin I is inactive as far as modulating blood pressure is concerned, whereas angiotensin II is a potent vasoconstrictor. As a matter of fact, angiotensin II turned out to be the most potent blood-pressure-raising substance in the human body. As a consequence, inhibition of angiotensin-converting enzyme would provide vasodilation and lower the blood pressure.
In 1965, John Vane (1982 Nobel laureate in medicine) was a professor at Oxford University. A Brazilian postdoctoral student of his, Sergio Ferreira, brought with him a dried extract of the venom of the poisonous Brazilian pit viper, Bothrops jararaca, which was the fruit of his Ph.D. thesis. The venom poison is known to reduce the blood pressure of its victims. In 1967, Vane persuaded his colleague Mick Bakhle to test Ferreira’s snake venom extract on an in vitro preparation of the ACE and found it to be a potent inhibitor. Injection of the snake venom into humans would surely result in fatal consequences; therefore the venom itself was not a viable drug. Vane was a consultant for the pharmaceutical company Squibb Institute, and he suggested that they study the snake venom extract. His idea was received with only lukewarm enthusiasm from Squibb’s marketing staff. The active principle of the snake venom extract consisted of peptides, which are not orally bioavailable because the acidic environment of the stomach induces a breakdown into constituent amino acids. Obviously, there would be a smaller market for a hypertension drug that had to be injected.
Fortunately, two bench scientists, biochemist David Cushman and organic chemist Miguel A. Ondetti, remained enthusiastic. In time they isolated a nonapeptide (a peptide with nine amino acids) that had a longer duration of action. They christened it teprotide. Squibb synthesized one kilogram of teprotide at the cost of some $50,000, a lofty sum at that time. Injection of teprotide into volunteers reduced blood pressure and confirmed that it was an ACE inhibitor in humans. With brilliant insight, Cushman and Ondetti chopped the teprotide molecule into some bare minimal fragments and obtained drugs with better oral activities. The breakthrough came when they replaced the carboxylate group with a thiol (-SH) and achieved a 2,000-fold increase in potency in ACE inhibition. The drug became the first oral ACE inhibitor, captopril. Squibb has sold it under the brand name Capoten since 1978. Captopril was the first commercially available ACE inhibitor and a market success; it contributed tremendously to the management of hypertension. Squibb arrived at captopril from only 60 compounds logically synthesized and tested. Ironically, Squibb had also set up a random screen for ACE inhibitors and tested more than 2,000 compounds from the Squibb library. None were active.
Captopril has a rapid onset of action, reaching maximum activity in 15-30 minutes, but the plasma half-life is only 2 hours. Therefore, captopril must be taken more than once a day. Other shortcomings of captopril are rashes and diminution or loss of taste perception, which may be attributed to the presence of the thiol functional group. Cough and angioedema are also side effects of ACE inhibitors.
The two discovers of captopril, Cushman and Ondetti, made significant contributions to medical science, not only by having discovered captopril but also by pioneering a revolutionary approach to drug discovery in the process. They exploited a three-dimensional protein structure to design an oral active drug. Their work ushered in a new technology called structure-based drug design (SBDD), which is now used throughout the pharmaceutical industry. In 1999, Cushman and Ondetti were honored with the Albert Lasker Award for Clinical Medical Research.
To make a better ACE inhibitor by improving captopril, a group of Merck scientists led by Arthur A. Patchett started to replace the thiol group with a carboxylate. The loss in potency of the carboxylate was compensated for by modification of the molecule elsewhere. They arrived at a very potent molecule, enalaprilat, which suffered poor oral bioavail-ability. They simply converted the acid into its corresponding ethyl ester, creating enalapril, a prodrug of enalaprilat, with excellent oral bioavail-ability. Enalapril is a prodrug because, when it enters the gut, it becomes hydrolyzed to the active drug, enalaprilat. Although enalapril is a «me-too» drug of captopril, it is better absorbed by the stomach. One advantage of a prodrug is the delay in onset of action, which can be beneficial for a drug that treats blood pressure. The longer duration of action allows a once-daily dosage. It is also devoid of the side effects associated with the thiol group, including bone marrow growth suppression (due to a decrease in circulating white blood cells), skin rash, and loss of taste. In 1981, Merck successfully completed the clinical trials, gained approval, and sold enalapril using the brand name Vasotec, which became their first billion-dollar drug in 1988. Another popular ACE inhibitor is Pfizer’s Accupril (quinapril hydrochloride).
Although early ideas about hypertension suggested that ACE inhibitors would be useful only in certain circumstances, this proved to be an oversimplification. ACE inhibitors have become an important class of drugs for controlling the commonly encountered form of hypertension. Moreover, ACE inhibitors have been proven beneficial to patients suffering from heart attacks, congestive heart failure, and possibly even atherosclerosis. A pharmacoeconomics study published in July 2005 calculated that the U.S. government would save money by giving away ACE inhibitors to seniors because the cost of the drugs is far less than the cost for treating the later-stage cardiovascular diseases.
Because angiotensin II is a potent vasoconstrictor, blocking its action would result in vasodilation. Dupont (a company that got its start with ni-troglycerin) exploited the angiotensin II receptor in the early 1980s. But Dupont was a chemical company and did not have expertise in clinical trials and marketing. They formed a 50-50 joint venture with Merck, establishing Dupont-Merck Pharmaceuticals. Angiotensin II receptor antagonist losartan (Cozaar) was the fruit of Dupont-Merck. Cozaar, launched in 1995, quickly established itself as one of the most important drugs for the treatment of high blood pressure. Cozaar, along with other drugs of this class, proved to be superior to ACE inhibitors because it did not cause the irritating cough that occurs in a small percentage of patients who take ACE inhibitors. Novartis’s top seller, valsartan (Diovan), is an angiotensin II receptor antagonist that generated $2.4 billion in sales in 2003. Other well-known angiotensin II receptor antagonists are Sanofi-Synthelabo’s irbesartan (Avapro), Astra-Zeneca’s candesartan (Atacand), Sankyo’s olmesartan medoxomil (Benicar), Sovay’s eprosartan (Teveten), and Boehringer Ingelheim’s telmisartan (Micardis).
