MEDICINAL CHEMISTRY

Structure-activity Relationships of ACE inhibitors:
Angiotensin converting enzyme is a stereoselective drug target. Since currently approved
ACE inhibitors act as either di - or tripeptide substrate analogs, they must contain a
stereochemistry that is consistent with the L-amino acids present in the natural substrates.
This was established very early in the development of ACE inhibitors when compounds
with carboxyl-terminal D-amino acids were discovered to be very poor inhibitors. It was
reported that a 100 to 1000 fold loss in inhibitor activity whenever the configuration of
either the carboxylate or the R, substituent was altered. The S, SS configuration seen in
enalapril and dicarboxylate inhibitors meets the above stated criteria and provides for
optimum enzyme inhibition.
Physicochemical Properties: Captopril (79) and fosinopril are acidic drugs, while all
other ACE inhibitors are amphoteric. The carboxylic acid attached to the N-ring is a
common structural feature in all ACE inhibitors. It has a pKa in the range of 2.5-3.5 and
will be primarily ionized at physiologic pH. As discussed above with enalapril, the pKa
and ionization of the secondary amine present in the dicarboxylate series depends upon
whether the adjacent functional group is in the prodrug or active form. In the prodrug
form, the amine is adjacent to an ester, is less basic, and is primarily unionized at
physiologic pH. Following bioactivation, the amine is adjacent to an ionized carboxylic
acid, which enhances both the basicity and ionization of the amine. Similarly, the basic
nitrogen enhances the acidity of the adjacent carboxylic acid such that it usually has a
lower pKa than the carboxylic acid attached to the N-ring. As an example, the pKa
values of enalapril are 3.39 and 2.30. These values correspond to the carboxylic acid on
the N-ring and the carboxylic acid adjacent to the amine, respectively.
Structure-activity Relationship of ACE Inhibitors
(CH 2) n
(101)
Zn 2+
O
Binding
Group N-ring HS
X
Zn 2+ Binding groups
A
H 2
C
H
C H N
COOH
a. The N-ring must contain a carboxylic acid to mimic the C-terminal carboxylate of
ACE substrates.
b. Large hydrophobic heterocyclic rings in the ~N-ring increase potency and alter
pharmacokinetic parameters.
C. Groups A, B, or C can serve as zinc binding groups.
d. The sulfhydryl group shows superior binding to zinc (Phe in carboxylate and
phosphinic acid side chain compensates for sulfhydryl group).
e. Sulfhydryl-containing compounds produce high incidence of skin rash and taste
disturbances.
f. Sulfhydryl-containing compounds can form disulfides, which may shorten duration
of action.
B
OH
P
O
C