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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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Varying mortality reduction among ACE inhibitors
From American Family Physician, 5/15/05 by Richard Sadovsky

When taken after an acute myocardial infarction, angiotensin-converting enzyme (ACE) inhibitors improve survival and reduce the risk of recurrence. This has been thought to be a class effect--i.e., all drugs in the class have the same beneficial outcomes. Because different ACE inhibitors vary in structure and potency, they may not be equally effective. Pilote and associates examined the one-year mortality rate of various ACE inhibitors when given to older persons after a first acute myocardial infarction.

A chart review was used to identify patients 65 years or older who filled at least one prescription for an ACE inhibitor within 30 days of discharge following an acute myocardial infarction. A total of 7,512 patients were selected and were grouped by ACE inhibitor. Patients who switched prescriptions during the first year were excluded. Enalapril was the most common prescription, followed by lisinopril.

Patients taking enalapril, fosinopril, captopril, or quinapril had higher mortality rates than those taking ramipril. No significant difference was shown between ramipril and lisnopril or perindopril. Readmissions for unstable angina and recurrent myocardial infarction were similar across all treatment groups.

The authors conclude that there is variation among ACE inhibitors, and that the one-year mortality rate is significantly lower in older persons who take ramipril after a first acute myocardial infarction than in those taking other ACE inhibitors. It is unclear what mechanism is responsible for this difference. More studies are needed to confirm these results.

Pilote L, et al. Mortality rates in elderly patients who take different angiotensin-converting enzyme inhibitors after acute myocardial infarction: a class effect? Ann Intern Med July 20, 2004;141:102-12.

EDITOR'S NOTE: In an editorial in the same journal, (1) Hennessy and Kimmel comment that the best way to evaluate drug effects in a pharmacologic class is to perform head-to-head randomized trials of clinical outcomes or validated surrogate endpoints. Because there are no validated surrogate endpoints for the mortality reduction proferred by ACE inhibitors, these trials cannot be used. Other studies are prone to bias. Hennessy and Kimmel point out that, in the above study, (2) there were variations in the point at which ACE inhibitors were started in each patient population, and they also note the higher proportion of patients receiving beta blockers and lipid-lowering drugs in the ramipril and perindopril groups. They conclude that the evidence is not sufficient to favor one ACE inhibitor over another on the basis of survival benefit after acute myocardial infarction; however, they recommend using only those ACE inhibitors that have been proven to increase survival rates for this indication.--R.S.

REFERENCES

(1.) Hennessy S, Kimmel SE. Is improved survival a class effect of angiotensin-converting enzyme inhibitors? Ann Intern Med 2004;141:157-8.

(2.) Pilote L, Abrahamowicz M, Rodrigues E, Eisenberg M J, Rahme EM. Mortality rates in elderly patients who take different angiotensin-converting enzyme inhibitors after acute myocardial infarction: a class effect? Ann Intern Med 2004;141:102-12.

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