Why renin inhibitors?

Angiotensin converting enzyme inhibitors are widely used in the treatment of hypertension and congestive heart failure. They are potent drugs and have few side effects. The search for potent and orally absorbable agents that either block the angiotensin II receptor or inhibit the catalytic action of renin has not been so successful. This paper reviews present efforts to develop renin inhibitors. Most of the work has been based on the design of peptide analogues of angiotensinogen, many of which contain the unusual amino acid statine (or one of its variants) in place of the scissile bond (the peptide bond that renin cleaves in angiotensinogen). Substitutions at other sites in the molecule determine potency and species selectivity; for example, substitutions at the carboxyl terminus permit the construction of potent renin inhibitors that contain fewer amino acid residues. Peptide analogues of the prorenin segment of the enzyme, however, are but weak inhibitors and show little promise. Progress has also been slow in efforts to understand the principles required in the synthesis of potent renin inhibitors with significant bioavailability after oral administration. Finally, the question of whether renin inhibitors will offer a clinical advantage over converting enzyme inhibitors has not been answered.