inhibitor that leads to a significant, short-duration lowering of the blood pressure
following intravenous injection. Two partially orally active renin inhibitors have been
designed and developed by medicinal chemists (remikiren (5.132), enalkiren (5.133));
these were cleverly designed as peptidomimetic transition state analogs of the cleavage
site of human angiotensinogen.
5.21.2.2 Angiotensin-Converting Enzyme Inhibitors
Angiotensin-converting enzyme inhibitors are among the most effective antihyperten-
sive drugs. The first such drug to be developed was teprotide (5.134), a nonapeptide
identical in sequence to peptides isolated from the venom of a Brazilian viper (Bothrops
jararaca). The four prolines and the pyroglutamate in this peptide make it resistant to
degradation, with the result that it has a long-lasting action but is not hypotensive in
normal animals. Teprotide competitively inhibits the degradation of angiotensin I by the
converting enzyme. Due to its peptide structure, it is not orally active and must be
administered intravenously.
In 1977, a new drug, captopril (5.135), (2S)-I-(3-mercapto-2-methylpropionyl)-
L-proline, was developed by Cushman, Ondetti, and coworkers. It shares many of the
actions of teprotide but may be administered orally and is more than 10 times as active,
with a KDof 1.7 × 10 −^9 M. Cushman and colleagues studied peptide analogs to gain an
improved understanding of ACE enzymatic properties and then combined the results of
these studies with the fact that ACE has properties similar to those of the carboxypep-
tidase A enzyme, another zinc-containing exopeptidase. Assembling this knowledge,
they postulated a model receptor of the enzyme active site, containing three principal
binding subdomains: a positively charged arginine residue, the positively charged Zn^2 +
cation, and a hydrophobic pocket. They set out to design compounds to fit into this
model receptor. An important starting point arose from the observation that D-2-
benzylsuccinic acid is a potent inhibitor of carboxypeptidase A. To exploit this, a
variety of analogs of 2-benzylsuccinic acid were prepared, including a family of
succinyl-L-proline analogs. Although bioactive, this family needs improvement in
terms of potency. To achieve this improvement, the succinyl-L-proline backbone was
altered to include a sulfhydryl group whose sulphur atom would enable enhanced
binding to the zinc atom within the ACE active site. This relatively simple bioisosteric
substitution (and the addition of a 2-D-methyl group) enhanced potency 1000-fold and
produced the clinical candidate molecule captopril.
Although the sulfhydryl group of captopril produced superb ACE inhibition, it also
caused two side effects which are sometimes seen with sulphur-containing drugs: skin
rashes and a metallic taste disturbance. In an attempt to overcome these side effects,
HORMONES AND THEIR RECEPTORS 373