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Fosinopril

Fosinopril is an angiotensin converting enzyme (ACE) inhibitor used for the treatment of hypertension and some types of chronic heart failure. Fosinopril is the first and only phosphonate-containing ACE inhibitor marketed. It is marketed by Bristol-Myers Squibb under the trade name Monopril®. more...

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Development

The development of fosinopril started from the observation of the hypotensive effects of phosphoramidon, an extract from the bacterium Streptomyces tanashiensis. Phosphoramidon was found to be a potent inhibitor of ACE. It was speculated that the phosphoramide moiety in the molecule was central to its inhibition of ACE. Further studies found that the phosphoramide moiety served the dual-purpose of interacting with the Zn²⁺ in ACE, as well as mimicking the transition-state of the natural substrate of ACE.

These discoveries led to the attempt to develop a new group of ACE inhibitors which contained the phosphoramide moiety. The initial lead proved to be very potent but unstable at physiological pH. Later compounds would have a phosphonate moiety (being more stable) in place of the phosphoramide. The lessons learnt in the development of enalapril and later ACE inhibitors were applied to the design and eventually fosinoprilat was developed.

Fosinoprilat and Fosinopril

Fosinoprilat proved to have the same problem as enalaprilat and the other carboxylate-containing ACE inhibitors (namely poor oral bioavailability). The solution, fortunately, was very similar - the addition of a hydrophobic side-chain to modulate the ionisation characteristics of the molecule. Thus fosinopril was developed. Fosinopril is administered as a prodrug and is converted in vivo to the active form fosinoprilat.

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Second-Generation ACE Inhibitors Work Best for Cardiovascular Disease - Statistical Data Included
From Family Pratice News, 4/1/00 by Mitchel L. Zoler

LAKE BUENA VISTA, FLA. -- Second-generation angiotensin converting enzyme inhibitors have supplanted the first-generation drugs for treating cardiovascular diseases.

The first-generation ACE inhibitors include captopril, enalapril, and lisinopril. The second-generation drugs include quinapril, ramiptil, fosinopril, and several others.

That's because the second-generation agents have much better tissue penetration, compared with the first-generation ACE inhibitors. "In our bodies, most of the ACE and angiotensin conversion occurs at the tissue level, and that's where we want the drugs to he," Dr. Carl J. Pepine said at a meeting sponsored by the American College of Cardiology.

Several features distinguish the two generations and help to explain their

different clinical effects, said Dr. Pepine, chief of the division of cardiovascular medicine at the University of Florida in Gainesville.

The second-generation drugs are much more lipophilic, which helps them penetrate tissues at much higher concentrations. These agents also bind to their target enzyme more tightly and wash out from the body more slowly, compared with first-generation drugs, which is why they are used once a day.

Although the first-generation ACE inhibitors are fine for controlling angiotensin conversion in plasma, it is the ACE in tissues that has a bigger impact on the long-term course of cardiovascular disease. Plasma ACE primarily mediates acute effects during emergency situations.

The different clinical effects of first- and second-generation ACE inhibitors were highlighted by the results of a recent study that compared captopril, quinapril, and placebo in patients who were scheduled to undergo coronary bypass surgery After 1 month of treatment with one of these three drugs, a small piece of each patient's internal mammary artery was harvested during surgery.

The arterial walls from patients treated with captopril had much higher levels of ACE activity compared with the patients treated with quinapril. This difference correlated with clinical effects: One year after surgery the quinapril-treated patients had significantly fewer rehospitalizations than the patients treated with captopril or with placebo, he said.

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