Molecular structure of captopril
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Captopril

Captopril is an Angiotensin-Converting Enzyme inhibitor (ACE inhibitor) used for the treatment of hypertension and some types of chronic heart failure. Captopril was the first ACE inhibitor developed and was considered a breakthrough both because of its novel mechanism of action and also because of the revolutionary development process. The original innovator drug Bristol-Myers Squibb's Capoten®. more...

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Clinical Use

Development of captopril

Captopril was invented in 1975 by three researchers at the American drug company Squibb (now Bristol-Myers Squibb) , Miguel Ondetti, Bernard Rubin and David Cushman. Squibb filed for American patent protection on the drug in February 1976 and U.S. Patent was 4,046,889 was granted in September 1977.

The development of captopril was amongst the earliest successes of the revolutionary concept of structure-based drug design. The renin-angiontensin-aldosterone system had been extensively studied in the mid-20th century and it had been decided that this system presented several opportune targets in the development of novel treatments for hypertension. The first two targets that were attempted were renin and ACE. Captopril was the culmination of efforts by Squibb's laboratories to develop an ACE inhibitor.

Ondetti, Cushman and colleagues built on work that had been done in the 1960s by the British Nobel laureate Sir John Vane when he was a researcher at the Royal College of Surgeons. Working with a Brazilian colleage, Sérgio Ferreira, Vane discovered a peptide in Brazilian viper venom which was a 'collected-product inhibitor' of angiotensin II. Captopril was developed from this peptide after it was found via QSAR-based modification that the terminal sulfhydryl-moiety of the peptide provided a high potency of ACE inhibition.

Capoten gained FDA approval in June 1981. The drug went generic in the U.S. in February 1996 as a result of the end of market exclusivity for Bristol-Myers Squibb.

Shortcomings

During Phase III/IV trials of captopril, it was found that captopril had some undesirable adverse effects. The most predominant of which included cough, rash and taste disturbances (metallic or loss of taste). Cough is an adverse effect common to all of the ACE inhibitors, but the rash and taste disturbances were attributed to the very sulfhydryl moiety which granted captopril its potency. An additional shortcoming of captopril is the short half-life, necessitating 2-3 times daily dosing.

The development of longer-acting ACE inhibitors lacking the sulfhydryl-moiety such as enalapril proved to be the downfall of captopril and, whilst it is still used, it is no longer amongst the more widely used ACE inhibitors.

Reference

  • Smith CG, Vane JR. The discovery of captopril. FASEB J 2003;17:788-9. Fulltext. PMID 12724335.

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ACE inhibitor protects diabetics' kidneys - angiotensin-converting-enzyme; captopril
From Science News, 11/13/93 by Richard Lipkin

People with insulin-dependent (juvenile-onset) diabetes - a disease that interferes with the metabolism of sugar, run about a 35 percent risk of getting kidney disease, or nephropathy.

Nephropathy, a progressive condition, can lead to complete kidney failure within 10 years, Diabetics with this complication are nine times more likely to die prematurely than diabetics without it.

However, a new study shows that a drug commonly used to control high blood pressure may also offer some protection against nephropathy.

Edmund J. Lewis, a physician at Rush-Presbyterian-St. Luke's Medical Center in

Chicago, and his colleagues report that captopril -- a type of angiotensin-convertlag-enzyme (ACE) inhibitor- "protects renal function in insulin-dependent diabetic nephropathy and is significantly more effective than blood-pressure control alone." Their report appears in the Nov. 11 NEW ENGLAND JOURNAL OF MEDICINE.

"We were struck by how positive the study's results are," Lewis says. "We found that ACE inhibitors retard kidney disease at all stages studied. The fact that there was a positive effect in patients with the most advanced disease was a surprise. Most people believe that once kidney disease has gone far, there's no stopping it."

The researchers studied 409 diabetics between December 1987 and October 1990. The patients, 18 to 49 years old, had insulin-dependent diabetes for at least seven years, with an onset before age 30, plus kidney disease, measured by protein excretions in their urine and elevated concentrations of serum creatinine, indications of kidney damage. In the doubleblind study, 207 patients took 25 milligrams of captopril three times a day, while 202 patients received placebo pills.

A total of 301 patients completed the study as planned; 58 patients required additional follow-up or were removed from the study for health reasons; and 50 underwent kidney dialysis, had a kidney transplant, or died.

Among the conclusions: "We found that captopril significantly retarded the rate of loss of renal function in this group of patients with diabetic nephropathy. In the captopril group, the risk of a doubling of the serum creatinine concentration was reduced by almost one-half, as was the combined risk of death, dialysis, and transplantation," the researchers state. And captopril's protective mechanism appears "independent of its antihypertensive properties."

The researchers believe that captoprii, like other ACE inhibitors, eases the pressure within the kidneys' many small filters, called glomeruli. "The blood vessels draining these filters, for unknown reasons, constrict in the diabetic state:' Lewis says. "This constriction causes the giomeruli's internal pressure to rise, which seems to cause scarring that leads to progressive renal failure."

A hormone produced in the kidney, called angiotensin II, controls this renal constriction, says Lewis. Captopril inhibits the hormone's production, thus allowing the pressure within the glomeruli to fall. Whether other ACE inhibitors will perform equally well remains an open question, he adds, "but the rationale behind the study suggests they could. We studied captopril because we'd had the most experience with it, but we don't know yet how other ACE inhibitors will do.

These findings could affect the treatment of the 14 million U.S. diabetics and the 100 to 150 million worldwide, says Sara King of the Juvenile Diabetes Foundation. About 10 percent of diabetics develop insulin-dependent diabetes, usually in childhood; the rest develop noninsulin-dependent diabetes, she notes. Although this study focused on juvenileonset diabetics, Lewis believes captopril may benefit adult-onset patients as well.

It's possible that diabetic nephropathy is now a preventable disease," says Nell Kurtzman, president of the National Kidney Foundation, "provided we start treatment early enough."

COPYRIGHT 1993 Science Service, Inc.
COPYRIGHT 2004 Gale Group

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