Development of other inhibitors has also been based on the concept of biproduct inhibition. Optimization of orientations of the C-terminus carboxyl and amide carbonyl for binding to the enzyme by incorporating some features of succiny-L-proline into an Ala-Pro 'backbone' led to the development of thiol-free inhibitors such as enalaprilat (8.49). This had a better side effect profile than captopril but was not active when given orally. The ethyl ester enalapril is well absorbed and is subsequently hydrolysed in vivo
to the active inhibitor enalaprilat. Enhancement of enzyme-inhibitor interactions by introduction of bulky hydrophobic groups at the C-terminal produced inhibitors such as quinaprilat (8.50), ramiprilat (8.51) and spiraprilat (8.52). A methyl sustituent on the Pj' residue enhances potency of inhibitors with proline at the C-terminal (e.g.
enalaprilat), and is built into compounds with large hydrophobic residues at the C-terminus such as cilazaprilat (8.53), lisinopril (8.54), benzeprilat (8.55) and perindoprilat (8.56). With these inhibitors, the larger group appears to be sufficient to fill the S1'-S2' pockets and give the right orientation to the remaining part of the molecule for interaction with the enzyme. The phosphonate containing inhibitor, fosinoprilat (8.57), as well as ceranapril (8.58), has features of both a bi-product inhibitor and the transition-state of the enzyme catalysed reaction. With the exception of captopril and lisinopril, all inhibitors in clinical use have to be given as ester pro-drugs for oral bioavailability. Apart from their use as antihypertensives, ACE inhibitors are proving to be particularly useful as an adjunct with diuretics or digoxin in the treatment of heart failure. They also appear to have a particular role in reducing blood pressure in patients with diabetic nephropathy.
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