researchers at Merck sought to replace the sulfhydryl group with a bioisosterically
equivalent carboxylate group that could bind to Zn^2 +. Thus they sought to design dicar-
boxylate-containing ACE inhibitors. As a prototypic structure around which to execute
this design strategy, they designed a model tripeptide in which the N-terminal residue
was isosterically replaced with an N-carboxymethyl group. An analog series based
upon this central pharmacophore structure yielded enalaprilat (5.136) as a clinical
candidate. Although it exhibited excellent activity when administered intravenously,
enalaprilat demonstrated unacceptably poor oral bioavailability. However, esterification
of enalaprilat produced enalapril (5.137), an agent with superior oral bioavailability.
Since enalapril needs de-esterification for bioactivation, it functions as a prodrug.
The success of enalapril led to a variety of other additional dicarboxylate inhibitors.
The first of these was lisinopril (5.138). This agent was developed at the same time as
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