ANGIOTENSIN CONVERTING ENZYME INHIBITORS

(ACEIs)

ACEIs is a zinc-containing dipeptidyl carboxypeptidase which block the angiotensin converting

enzyme which ultimately inhibit the conversion of angiotensin II from angiotensin I. It is a class
of medication used primarily for the treatment of high blood pressure  and heart failure.

MECHANISM OF ACTION:
The ACE inhibitors lower blood pressure by reducing peripheral vascular resistance. Block the
ACE that cleaves angiotensin I to form the potent vasoconstrictor angiotensin II. It decrease the
angiotensin II and increase the bradykinin levels.

CLASSIFICATION OF ACEIs:
It include the following drugs:

LINSOPRIL:
It is a lysine derivative of enalaprilat, the active metabolite of enalapril. Like all ACE inhibitors, it
is an active site-directed inhibitor of the enzyme, with the zinc ion used in an effective binding
interaction at a stoichiometric ratio of 1:1. The pharmacological effects of lisinopril are similar
to those of captopril and enalapril.

QUINAPRIL HYDROCHLORIDE:
Quinapril hydrochloride forms the diacid quinaprilate in the body. It is more potent than
captopril and equipotent to the active form of enalapril.
RAMIPRIL:
It is hydrolyzed to ramiprilat, its active diacid form, faster than enalapril is hydrolyzed to its
active diacid form. Peak serum concentrations from a single oral dose are achieved between 1.5
and 3 hours. The ramiprilate formed completely suppresses ACE activity for up to 12 hours,
with 80% inhibition of the enzyme still observed after 24 hours.

FOSINOPRIL SODIUM:
It is a phosphorus-containing ACE inhibitor. It is inactive but serves as a prodrug, being
completely hydrolyzed by intestinal and liver enzymes to the active diacid fosinoprilat.

TRANDOLAPRIL:
It is an indole-containing ACE inhibitor that is structurally related to most of the preceding
agents discussed. Enalapril is very similar to trandolapril, with the primary difference occurring
in the heterocyclic systems. The pyrrolidine of enalapril has been replaced with an
octahydroindole system. Much like enalaprilate, trandolapril must be hydrolyzed to
tranolaprilate, which is the bioactive species.

SAR OF ACE INHIBITORS:

a. The N-ring must contain a carboxylic acid to mimic the C-terminal carboxylate of ACE substrates.

b. Large hydrophobic heterocyclic rings (i.e., the N-ring) increase potency and alter pharmacokinetic
parameters.

c. The zinc binding groups can be either sulfhydryl (A), a carboxylic acid (B), or a phosphinic acid (C).

d. The sulfhydryl group shows superior binding to zinc (the side chain mimicking the Phe in carboxylate
and phosphinic acid compounds partially compensates for the lack of a sulfhydryl group).

e. Sulfhydryl-containing compounds produce high incidence of skin rash and taste disturbances.

f. Sulfhydryl-containing compounds can form dimers and disulfides, which may shorten duration of
action.

g. Compounds that bind to zinc through either a carboxylate or phosphinate mimic the peptide
hydrolysis transition state and enhance binding.

h. Esterification of the carboxylate or phosphinate produces an orally bioavailable prodrug.

i. X is usually methyl to mimic the side chain of alanine. Within the dicarboxylate series, when X equals
n-butylamine (lysine side chain), this produces a compound that does not require prodrug for oral
activity.

j. Optimum activity occurs when stereochemistry of inhibitor is consistent with L-amino acid
stereochemistry present in normal substrates.

REFERENCES:

https://www.slideshare.net/IrresoluteTanvir/ace-inhibitors-drugs

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