ACE inhibitors

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Hypertension, high blood pressure, is a major cause of heart disease and stroke, both of which are called vascular disease.

While hypertension can be caused by blood vessel obstruction, the most common cause results from an imbalance in the biochemicals which regulate blood pressure. The mechanism of regulation is complex and key players in this regulatory scheme are a group of peptides and at least one steroidal hormone, aldosterone.

The peptide hormones angiotensin II and bradykinin have receptors in the blood vessels which lead to their constriction, or dilation, respectively. Aldosterone maintains fluid balance by controlling Na+/K+. The Scheme below shows how Angiotensin II is biosynthesized from a precursor peptide called angiotensinogen through the action of two enzymes, rennin and angiotensin converting enzyme (ACE).

Synthesis of angiotensin II.jpg

The first step involving renin, produces angiotensin I, which has little known biological activity. ACE converts angiotensin I into angiotensin II by cleaving the dipeptide form it. Angiotensin II is not only a vasoconstrictor but it stimulates the release of aldosterone, and deactivates bradykinin by cleaving two C-terminal dipeptides from it. All of these processes increase blood pressure. Inhibitors of ACE, therefore, have tremendous potential for reducing hypertension.

The first ACE inhibitors to be marketed was called captopril.

Problems with Captopril were:

  • Loss of taste
  • Rashes
  • Rapidly metabolized

This indicated a possible problem with the sulfhydryl group (SH) group.

More active site modeling led to enalaprilat, but this compound was poorly adsorbed due to the presence of the two carboxy groups which can ionize. To remedy this problem, its ethyl ester was synthesized. It is called enalpril and is an example of a prodrug. Such drugs undergo a biochemical transformation which converts them into their active form. In this case, the transformation is the enzymatic hydrolysis of the ethyl ester by an esterase to give enalaprilat.