Enalaprilat ethyl ester

Enalipril (= Enalaprilat Synthetic Enalaprilat ethyl ester ACE [major antihypertensive... 

To improve the oral properties of enalaprilat, Patchett and colleagues turned to a prodrug approach. Esters were made of only one and of both carboxyls, and fortunately only esters of the N-carboxyalkyl group were needed for good oral absorption. When the proline carboxyl is esterified, the resultant inhibitor would have been difficult to formulate, since closure to a diketopiperazine easily takes place. Although various esters were tried, none were clearly superior to the ethyl ester 20 (Table IV). 

It is interesting to observe that the loss in affinity caused by the replacement of the mercapto function by a carboxyl rest was compensated, thanks to an additional hydrophobic interaction. Thus, scientists from Merck developed enal-aprilat 6a, a compound of comparable effectiveness and for which the additional hydrophobic interaction is provided by a phenethyl rest. But enalaprilat is poorly absorbed orally therefore the commercial compound is enalapril 6b, the corresponding ethyl ester. 

Enalapril, (S)-l-[N-(ethoxycarbonyl)-3-phenylpropyl]-L-alanyl-L-proline, an orally active inhibitor of the angiotensinconverting enzyme (ACE). After oral administration, the prodrug enalapril (ICso = 1.2 X 10 M) is primarily bioactivated in the liver by hydrolysis of the ethyl ester to yield enalaprilat (IC50 =... 

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