Second-Generation ACE Inhibitors

Since 1975, researchers at the American company Merck had been working on improvements to captopril, which is associated with a number of undesirable side-effects these are attributed in part to the free mercapto group haemato- 

However, it turned out that enalaprilate possessed a poor oral bioavaUability in rats, dogs and humans. Only the development of a pro-drug, the ethyl ester, solved this problem. After enalapril is absorbed, esterases then release the active agent. Enalapril itself binds insufficiently to the enzyme. [14] 

Whereas Iisinoprii is more slowly and to a lesser extent absorbed than enalapril, it offers the advantage that no metabolic activation is required. [14] 

The convergent synthesis of these compounds is rather simple. On the one side, the required a-keto ester may be synthesised from diethyl oxalate by a Grignard reaction. On the other side, alanine or trifluoroacetyllysine is coupled with proline via the oxazolidine-2,5-dione (the so-called Leuchs anhydride ). The two halves are combined by reductive amination. The diastereoselectivity of the hydrogenation is dependent on the choice of catalyst. With Raney nickel, the diastereoselectivity lies in case of enalapril at 87 13 and for Iisinoprii at 95 5 in favour of the desired diastereomers. In the case of Iisinoprii, there follows a final hydrolysis of the ester and amide function. The active material is ultimately purified by crystallisation. 

The importance of proline as the C-terminal amino acid in ACE inhibitors is best seen, if this building block is removed from enalaprUate that leads to a complete loss of activity. If the terminal carboxylic acid function is converted into the corresponding amide, or if proline is replaced by phenylalanine, this results in relatively poor affinity as well. However, good activity is found with bicyclic proline derivatives, which are optimised for their interactions in the S2-pocket (Fig. 5.15). [14,15] Many of the active compounds following on from enalapril possess this structural motif, e.g. ramiprilate (Hoechst) and tran-dolaprUate (Roussel) (Fig. 5.16). Like the majority of ACE inhibitors approved up to 2003, these compounds are administered as pro-drugs (ethyl esters). 

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Figure 6. Effect of a second-generation ACE inhibitor, temocapril, on tumor blood flow. Note the great difference in flow rate in normal organs (A) vs that in tumor (B). Tumor blood flow was most affected by elevating blood pressure. The tumor used was LY80 in rats. (Adapted fh)m ref. 39).

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