Angiotensin Converting Enzyme Inhibitors

The discovery of ACEIs has been made possible by the finding of Ferreira et a/. in Brazil that the venom of a Brazilian pit viper contains peptides that enhance the vasodilator effect of bradykinin by inhibiting its degradation. Erdos et a/. found that the same enzyme that degrades bradykinin also converts Ang I to Ang II. Fereirra's peptides were expected not only to enhance bradykinin, but also to block the conversion of Ang I to Ang II. One of these, teprotide, was tested in animals and eventually humans, and found to inhibit ACE and to lower arterial pressure. Ondetti and Cushman at Squibb analyzed the structural requirements for the ACEI activity of teprotide, identified the active site of the enzyme, and designed a small molecule, a nonpeptide that inhibited ACE. Subsequent chemical optimization of this molecule led to the development of the first therapeutically useful ACEI, captopril (Table 5). The advantages of captopril and other ACEIs in the treatment of hypertension include their effectiveness in all types of hypertension, and the relative freedom from side effects. The major side effect of ACEIs is cough caused by bradykinin that accumulates due to inhibition of its degradation by the ACEIs. Another side effect is hyperkalemia; ACEIs should not be administered with K+-retaining diuretics or with K+ supplements.

Table 5 Structures, in vitro IC50s, eilimination half-life (f1/2), bioavailability, and clinical doses of commonly used ACEIs

Drugs

Structure

In vitro ACE inhibition IC50 (nM) tip (h)

Bioavailability (%) Clinical doses (mg)

Directly acting

Captopril H ┬╗CH,

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