Enalapril Vasotec

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Ball-and-Stick Model c2h5o2c ch3

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Space-filling Model

Year of discovery: 1981; Year of introduction: 1985 (Merck); Drug category: Angiotensin-Converting enzyme (ACE) inhibitor; Main uses: Treatment of hypertension, congestive heart failure and atherosclerosis; Related drugs: Captopril (Captopril), Ramipril (Altace), Quinapril (Accupril), Perindopril (Aceon), Lisinopril (Prinivil, Zestoretic), Benazepril (Lotensin).

Angiotensin II is a very potent human blood pressure regulator that causes contraction of blood vessels and an increase in blood pressure. Lowering angiotensin II levels reduces blood pressure.

The history of angiotensin II dates back to 1898, when Robert Tigerstedt, a physiologist at the Karolinska Institute in Stockholm, discovered that crude extracts of the kidney contained a substance that led to increased blood pressure in laboratory animals. He named this substance renin.

During the following 100 years it was revealed that renin is an enzyme that is part of the complex renin-angiotensin system. Renin catalyzes the transformation of angiotensinogen, a protein produced in the liver, into angiotensin I, which has only a modest effect on blood pressure, but is the direct precursor of angiotensin II, a very potent pressor substance. This reaction is effected in the body by the angiotensin-converting enzyme (ACE). In 1967, John Vane and Sergio Ferreira at Oxford University found that the dried extract of Brazilian pit viper venom, which was known to reduce blood pressure, acts as a potent inhibitor of ACE. Vane, who was a consultant at the pharmaceutical company Squibb (now Bristol-Myers Squibb) at the time, suggested that the company investigate the venom's antihypertensive effect. Because the active peptides of the venom extract are unstable in the stomach, they were not orally active. However, chemists at the Squibb Co. succeeded in designing a non-peptide molecule that showed high inhibitory activity and excellent oral bioavailability. This substance, named captopril, entered the market in 1978 under the brand name Capoten, as the first commercially available ACE inhibitor for the treatment of hypertension. This drug became a huge therapeutic success, but because it had to be taken twice daily, it was overtaken by once-a-day relatives such as enalapril (Merck).

Enalapril is an orally active prodrug that is converted into the active drug, enalaprilat, in the gut. The prodrug to drug bioconversion involves the change of the carboxyethyl (COOC2H5) group of enalapril (shown in red in the above structure) to the carboxyl (COOH) of enalaprilat. Although enalaprilat is a very potent ACE inhibitor, it is not active when taken orally because of poor absorption.1^ Enalapril gained FDA approval in 1985 and became a billion-dollar drug a few years later. The specific mode of binding of enalapril to the ACE enzyme was determined using a high resolution X-ray crystal structure. The close-up image below shows enalaprilat directly interacting with the catalytic Zn active site of the enzyme.3

ion at the ion at the

1. Drugs 1986, 31. 198-248; 2. Drugs 1992, 43. 346-381; 3. Biochemistry 2004, 43, 8718-8724 (1UZE); Rets. p. 83


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