Medicinal

Chemistry Course

Angiotensin conver-ng enzyme

inhibitors

Muhammad Aswad
 The renin-angiotensin pathway
•  The renin-angiotensin system is a complex, highly
regulated pathway that is integral in the
regula8on of blood volume, electrolyte balance,
and arterial blood pressure.
•  It consists of two main enzymes, renin and
angiotensin-conver8ng enzyme (ACE), the
primary purpose of which is to release
angiotensin II from its endogenous precursor,
angiotensinogen
•  Angiotensin II is a potent vasoconstrictor that
affects peripheral resistance, renal func8on, and
cardiovascular structure
 Angiotensin I

ACE

Angiotensin II
•  The treatment of hypertension and conges8ve heart
failure (CHF) has improved significantly with the
introduc8on of angiotensin- conver8ng enzyme (ACE)
inhibitors, angiotensin receptor blockers, and calcium
channel blockers.
•  The SARs and structural modifica8ons of these agents
have produced major therapeu8c advances.
•  For example, more than 25 years ago, captopril was
the first ACE inhibitor to be developed. Subsequent
molecular modifica8ons led to the development of
newer agents, such as lisinopril.
•  Although lisinopril exerts comparable ACE inhibi8on, it
possesses a superior pharmacokine8c profile. Instead
of having to administer captopril three 8mes daily,
lisinopril can be administered once daily.
•  Administering an ACE inhibitor such as
lisinopril once daily results in greatly
enhanced medica8on compliance.
•  The therapeu8c outcomes of pa8ents with
hypertension and CHF have improved
immensely as a result.
•  Similar molecular enhancements have been
made with angiotensin receptor blockers and
calcium channel blockers.
•  The applica8on of basic science in modifying
the chemical structure of these agents has
ul8mately resulted in pa8ents living longer
and suffering fewer cardiovascular events,
such as myocardial infarc8on or worsening
CHF.
•  Importantly, their day-to-day quality of life is
preserved as well.
 Ac-ons and Proper-es of Renin-
Angiotensin Pathway Components

•  Renin is an aspartyl protease that determines
the rate of angiotensin II produc8on
•  It is a much more specific enzyme than ACE.
•  Its primary func8on is to cleave the Leu−Val
bond at residues 10 and 11 of angiotensinogen.
•  The s8mula8on of renin release is controlled
very closely by hemodynamic, neurogenic, and
humoral signals.
 Angiotensin Conver-ng Enzyme
•  ACE, also known as kininase II, is a zinc
protease that is under minimal physiological
control.
•  The only structural feature required by ACE is
that the penul8mate amino acid in the
pep8de substrate cannot be proline.
•  For this reason, angiotensin II, which contains
a proline in the penul8mate posi8on, is not
further metabolized by ACE
Bradykinin-ACE rela8onship and renin-
angiotensin pathway
 Bradykinin
•  Bradykinin is a nonapep8de that acts locally to
–  produce pain,
–  cause vasodila8on,
–  increase vascular permeability
–  s8mulate prostaglandin synthesis, and
–  cause bronchoconstric8on.
•  Similar to angiotensin II, bradykinin is produced by
proteoly8c cleavage of a precursor pep8de.
•  Cleavage of kininogens by the protease kallikrein produces
a decapep8de known as either kallidin or lysyl-bradykinin.
•  Subsequent cleavage of the N-terminal lysine by
aminopep8dase produces bradykinin.
•  The degrada8on of bradykinin to inac8ve pep8des occurs
through the ac8ons of ACE.
•  ACE not only produces a potent vasoconstrictor but also
inac8vates a potent vasodilator
 Angiotensin II
•  Angiotensin II is the dominant pep8de
produced by the renin-angiotensin pathway.
•  It is a potent vasoconstrictor that increases
total peripheral resistance through a variety of
mechanisms:
–  direct vasoconstric8on,
–  enhancement of both catecholamine release and
neurotransmission within the peripheral nervous
system, and
–  increased sympathe8c discharge.
•  The result of all these ac8ons is a rapid pressor
response.

 Angiotensin II
•  Angiotensin II causes a slow pressor response,
resul8ng in a long term stabiliza8on of arterial
blood pressure.
•  This long-term effect is accomplished by the
regula8on of renal func8on. Angiotensin II
directly increases sodium reabsorp8on in the
p r o x i m a l t u b u l e . I t a l s o a l t e r s r e n a l
hemodynamics and causes the release of
aldosterone from the adrenal cortex.
•  Finally, angiotensin II causes the hypertrophy and
remodeling of both vascular and cardiac cells
through a variety of hemodynamic and
nonhemodynamic effects
 Angiotensin III and 1−7
•  Although secondary pep8des, angiotensin III
and angiotensin 1-7, also are thought to
contribute to the overall effects of the renin-
angiotensin pathway
•  Angiotensin III is equipotent with angiotensin II
in s8mula8ng aldosterone secre8on; however,
it is only 10 to 25% as potent in increasing blood
pressure.
•  In contrast, angiotensin 1-7 does not cause either
aldosterone secre8on or vasoconstric8on, but it
does have potent effects that are dis8nct from
those of angiotensin II.
•  Similar to angiotensin II, angiotensin 1-7 causes
neuronal excita8on and vasopressin release.
Addi8onally, it enhances the produc8on of
prostaglandins via a receptor-mediated process
that does not involve an increase in intracellular
calcium levels.
•  It has been proposed to be important in the
modula8on of cell-to-cell interac8ons in
cardiovascular and neural 8ssues
 Role of The Renin-Angiotensin Pathway in
Cardiovascular Disorders
pathway is central to
•  Because the renin-angiotensin
the maintenance of blood volume, arterial blood
pressure, and electrolyte balance, abnormali8es in this
pathway can contribute to a variety of cardiovascular
disorders.
•  Overac8vity of this pathway can result in hypertension
or heart failure
•  Abnormally high levels of angiotensin II can contribute
to hypertension through both rapid and slow pressor
responses.
•  Addi8onally, high levels of angiotensin II can cause
cellular hypertrophy and increase both a[erload and
wall tension.
•  All of these events can cause or exacerbate heart
failure.
 Drug Therapy Affec-ng The Renin-
Angiotensin Pathway
• 
Because angiotensin II produces the majority of the effects
a\ributed to the renin-angiotensin pathway, compounds
that can block either the synthesis of angiotensin II or the
binding of angiotensin II to its receptor should a\enuate
the ac8ons of this pathway.
•  Indeed, enzyme inhibitors of both renin and ACE, as well as
receptor antagonists of angiotensin II, have all been shown
to produce beneficial effects in decreasing the ac8ons of
angiotensin II.
•  Inhibitors of ACE were the first class of compounds to be
marketed. This occurred in 1981 with the approval by the
U.S. Food and Drug Administra8on of captopril.
•  Fourteen years later, losartan was approved as the first
angiotensin II receptor blocker (previous referred to as an
angiotensin II receptor antagonist).
Development of Orally Ac-ve Renin Inhibitors

•  Renin is a very specific enzyme.
•  The octapep8de, H-P-F-H-L-L-V-Y, is the
smallest substrate recognized by the enzyme
and is similar to the eight-amino-acid
sequence, H6-P7-F8-H9-L10-V11-I12-H13, which is
found in angiotensinogen.
•  Using this octapep8de, Boger replaced the
labile L-L bond with the stable dipep8de
mimic sta8ne and replaced the two C-terminal
residues (V–Y) with similar hydrophobic amino
acids (L-F).
•  The resul8ng compound,
•  N-isovaleryl-H-P-F-H-Sta-L-F-NH2 (SCRIP)
•  showed effec8ve, although short-lived, inhibi8on
of renin when given intravenously (IV).
•  Infusion experiments with SCRIP were the first to
demonstrate that a small molecule renin inhibitor
could maintain a lowered blood pressure for an
extended period of 8me.
•  Suscep8bility to proteoly8c cleavage, however,
limited the therapeu8c u8lity of SCRIP and other
analogous pep8des.
•  Structure–ac8vity studies with SCRIP revealed that
the N-terminal H-P-F sequence could be replaced
with an acylated phenylalanine or tyrosine without
any significant loss in inhibitor ac8vity.
•  Addi8onal changes to SCRIP resulted in the clinical
drug candidate enalkiren, also known as A-64662
•  The his8dine residue (His 6 ), which is present in
angiotensinogen and all previous inhibitors, was thought to
be essen8al for enzyme recogni8on and was le[
unchanged.
•  The acylated tyrosine protects the compound from
aminopep8dase enzymes and also contributes to enzyme
ac8ve-site recogni8on.
•  The remainder of the molecule is a stable dipep8de
isostere.
•  The cyclohexylmethylene and iso-butyl side chains are
lipophilic and approximate the lipophilic side chains
present in Leu10 and Val11 of angiotensinogen.
•  Addi8onally, the use of a C-terminal alcohol instead of a C-
t e r m i n a l c a r b o x y l a t e p r o t e c t s e n a l k i r e n f r o m
carboxypep8dase enzymes
•  Enalkiren has been extensively studied in preclinical and
clinical trials and has been shown to be efficacious if given
IV. It lacks significant bioavailability, however, mainly
because of a lack of lipid solubility
•  A more lipophilic analogue, zankiren (A-72517), has
demonstrated increased oral bioavailability and
efficacy.
•  Preclinical and clinical trials with orally administered
zankiren showed good bioavailability and significant
reduc8on in blood pressure.
•  Zankiren has since been withdrawn from clinical trials
for undisclosed reasons
•  However, the FDA recently approved Aliskiren
(Tektournan), the first, non-pep8dic orally ac8ve renin
inhibitor.
•  It is approved for the treatment of hypertension and
will be available for use in 2007
Aliskiren (Tektournan®)
 Angiotensin-Conver-ng Enzyme
Inhibitors
• 

Currently, there are 11 ACE inhibitors approved for
therapeu8c use in the United States.
•  These compounds can be subclassified into three
groups based on their chemical composi8on:
– Sulhydryl-containing inhibitors (exemplified by
captopril),
– Dicarboxylate-containing inhibitors (exemplified
by enalapril), and
– Phosphonate-containing inhibitors (exemplified
by fosinopril).
 Angiotensin-Conver-ng Enzyme
Inhibitors

•  Captopril and fosinopril are the lone representa8ves of
their respec8ve chemical subclassifica8ons, whereas
the majority of the inhibitors contain the dicarboxylate
func8onality.
•  All of these compounds effec8vely block the
conversion of angiotensin I to angiotensin II and have
similar therapeu8c and physiological effects.
•  The compounds differ primarily in their potency and
pharmacokine8c profiles.
•  Addi8onally, the sulhydryl group in captopril is
responsible for certain effects not seen with the other
agents.
 SulXydryl-Containing Inhibitors:
Development of Captopril
•  that the venom of the South
In 1965, Ferreira et al. reported
American pit viper (Bothrops jararaca) contained factors that
poten8ated the ac8on of bradykinin.
•  These factors, originally designated as bradykinin-poten8a8ng
factors (BPFs), were isolated and found to be a family of pep8des
containing 5 to 13 amino acid residues.
•  Their ac8ons in poten8a8ng bradykinin were subsequently linked
to their ability to inhibit the enzyma8c degrada8on of bradykinin.
•  Soon therea[er, Bakhle et al. reported that these same pep8des
also inhibited the enzyma8c conversion of angiotensin I to
angiotensin II.
•  This la\er enzyme, ACE, is now known to be iden8cal with the
former bradykininase enzyme (kininase II).
•  Even at the 8me of these ini8al discoveries, however, BPFs were
seen as lead compounds for the development of new
an8hypertensive agents, because they possessed dual ac8vi8es—
inhibi8on of the degrada8on of bradykinin, a potent vasodilator,
and inhibi8on of the biosynthesis of angiotensin II, a potent
vasoconstrictor
•  A nonapep8de, SQ 20,881 (tepro8de), isolated from
the original BPFs had the greatest in vivo potency in
inhibi8ng ACE and was shown to consistently lower
blood pressure in pa8ents with essen8al hypertension.
•  It also exerted beneficial effects in pa8ents with heart
failure; however, because of its pep8de nature and
lack of oral ac8vity, tepro8de had limited ac8vity in the
therapeu8c treatment of these diseases
•  Cushman, Ondel, and coworkers used SQ
20,881 and other pep8de analogues to provide
an enhanced understanding of the enzyma8c
proper8es of ACE.
•  U s i n g k n o w l e d g e o f s u b s t r a t e - b i n d i n g
specifici8es and the fact that ACE has proper8es
similar to those of pancrea8c carboxypep8dases,
these researchers developed a hypothe8cal
model of the enzyme ac8ve site.
•  Carboxypep8dase A, like ACE, is a zinc-containing
exopep8dase.
•  The binding of a substrate to carboxypep8dase A
involves three major interac8ons
 Features at carboxypep-dase A
•  First, the nega8vely charged carboxylate
terminus of the amino acid substrate binds to the
posi8vely charged Arg145 on the enzyme.
•  Second, a hydrophobic pocket in the enzyme
provides specificity for a C-terminal aroma8c or
nonpolar residue.
•  Third, the zinc atom is located close to the labile
pep8de bond and serves to stabilize the
nega8vely charged tetrahedral intermediate,
which results when a molecule of water a\acks
the carbonyl bond between the C-terminal and
penul8mate amino acid residues
 Features at ACE
•  Similarly, the binding of substrates to ACE was
proposed to involve three or four major interac8ons.
•  First, the nega8vely charged carboxylate terminus of
angiotensin I and other substrates was assumed to
occur via an ionic bond with a posi8vely charged amine
on ACE.
•  Second, the role of the zinc atom in the mechanism of
ACE hydrolysis was assumed to be similar to that of
carboxypep8dase A. Because ACE cleaves dipep8des
instead of single amino acids, the posi8on of the zinc
atom was assumed to be located two amino acids
away from the ca8onic center for it to be adjacent to
the labile pep8de bond.
•  Third, the side-chains R1 and R2 could contribute
to the overall binding affinity; however, ACE,
unlike carboxypep8dase A, does not show
specificity for C-terminal hydrophobic amino
acids and was not expected to have a
hydrophobic binding pocket.
•  Finally, the terminal pep8de bond is nonlabile
and was assumed to provide hydrogen bonding
between the substrate and ACE.
 Development of D-2-benzylsuccinic acid
•  The development of captopril and other orally ac8ve ACE inhibitors
began with the observa8on that D-2-benzylsuccinic acid was an
extremely potent inhibitor of carboxypep8dase A.
•  The binding of this compound to carboxypep8dase A is very similar to
that seen for substrates with the excep8on that the zinc ion binds to a
carboxylate group instead of the labile pep8de bond.
•  Byers and Wolfenden proposed that this compound is a by-product
analogue that contains structural features of both products of pep8de
hydrolysis. Most of the structural features of the compound are
iden8cal to the terminal amino acid of the substrate, whereas the
addi8onal carboxylate group is able to mimic the carboxylate group
that would be produced during pep8de hydrolysis.
•  Applying this concept to the hypothe8cal model of ACE described
above resulted in the synthesis and evalua8on of a series of succinic
acid deriva8ves (Fig. 28.6B). Because proline was present as the C-
terminal amino acid in SQ 20,881 as well as in other potent, inhibitory
snake venom pep8des, it was included in the structure of newly
designed inhibitors.
 Inhibitor binding models of (A) D-2-benzylsuccinic acid to
carboxypep-dase A and (B) succinic acid deriva-ves to ACE.

•  The first inhibitor to be synthesized and tested was
succinyl-L-proline.
•  This compound proved to be somewhat disappoin8ng.
Although it provided reasonable specificity for ACE, it
was only approximately 1/500 as potent as SQ 20,881.
•  Subs8tu8on of other amino acids in place of
proline produced compounds that were even
less potent; hence, all subsequent SAR studies
were conducted using analogues of L-proline.
•  The addi8on of a methyl group to the 2
posi8on of succinyl-L-proline to mimic the
amino acid side chain, R2, of the substrate
enhanced ac8vity but only marginally. D-2-
Methylsuccinyl-L-proline had effects similar to
SQ 20,881 but was s8ll only 1/300 as potent.
•  The D-isomer, rather than the L-isomer normally seen for amino
acids, was necessary because of the isosteric replacement of an
NH2 with a CH2 present in succinyl-L-proline.
•  A comparison of the R2 group of the substrate with the methyl
group of D-2-methylsuccinyl-L-proline, illustrates that this methyl
group occupies the same binding site as the side chain of an L-
amino group.

•  One of the most important altera8ons to succinyl-L-proline was the
replacement of the succinyl carboxylate with other groups having
enhanced affinity for the zinc atom bound to ACE.
•  Replacement of this carboxylate with a sulhydryl group produced
3-mercaptopropanoyl- L-proline. This compound has an IC50 value
of 200 nM and is greater than 1000-fold more potent than succinyl-
L-proline.
•  Addi8onally, it is 10- to 20-fold more potent than SQ 20,881 in
inhibi8ng contrac8le and vasopressor responses to angiotensin I.
•  Addi8on of a 2-D-methyl group further enhanced ac8vity.
•  The resul8ng compound, captopril is a compe88ve inhibitor of ACE
with a Ki value of 1.7 nM and was the first ACE inhibitor to be
marketed.
•  The sulhydryl group of captopril proved to be
responsible not only for the excellent inhibitory ac8vity
of the compound but also for the two most common
side effects, skin rashes and taste disturbances (e.g.,
metallic taste and loss of taste).
•  These side effects usually subsided on dosage
reduc8on or discon8nua8on of captopril.
•  They were a\ributed to the presence of the sulhydryl
group, because similar effects had been observed with
penicillamine, a sulhydryl containing agent used to
treat Wilson's disease and rheumatoid arthri8s
 Dicarboxylate-Containing Inhibitors
Development of Enalapril

•  Researchers at Merck sought to develop
compounds that lacked the sulhydryl group of
captopril yet maintained some ability to chelate
zinc.
•  Compounds having the general structure shown
below were designed to meet this objec8ve.

•  These compounds are tripep8de substrate analogues in
which the C-terminal (A) and penul8mate (B) amino acids
are retained but the third amino acid is isosterically
replaced by a subs8tuted N-carboxymethyl group (C).
•  Similar to the results seen in the development of captopril,
C-terminal proline analogues provided op8mum ac8vity
•  The use of a methyl group at R3 (i.e., B = Ala)
and a phenylethyl group at R4 resulted in
enalaprilat
•  Enalaprilat, with a Ki of 0.2 nM, was
approximately 10-fold more potent than
captopril
•  The enhanced binding was proposed to be
caused by the ability to mimic the transi8on state
of angiotensin I hydrolysis.
•  Enalaprilat possess a tetrahedral carbon in place
of the labile pep8de bond
•  The secondary amine, the carboxylic acid, and
phenylethyl groups all contribute to the overall
binding of the compound to ACE.
•  The secondary amine is located at the same
posi8on as the labile amide nitrogen, the ionized
carboxylic acid can form an ionic bond with the
zinc atom, and the phenylethyl group mimics the
hydrophobic side chain of the Phe amino acid,
which is present in angiotensin I.
•  Despite excellent IV ac8vity, enalaprilat has very poor oral
bioavailability.
•  Esterifica8on of enalaprilat produced enalapril, a compound with
superior oral bioavailability.
•  The combina8on of structural features in enalaprilat, especially the
two carboxylate groups and the secondary amine, are responsible
for its overall low lipophilicity and poor oral bioavailability.
•  Zwi\erion forma8on also has been suggested to contribute to the
low oral ac8vity, and a comparison of the pKa values for the
secondary amine of enalaprilat and enalapril supports this
explana8on.
•  Ioniza8on of the adjacent carboxylate in enalaprilat greatly
enhances the basicity of the secondary amine such that the pKa of
the amine in this compound is 8.02, whereas in enalapril, it is only
5.49.
•  Thus, in the small intes8ne, the amine in enalaprilat will be
primarily ionized and form a zwi\erion with the adjacent
carboxylate, but the amine in enalapril will be primarily un-ionized (
 Addi8onal dicarboxylate inhibitors
•  Eight other dicarboxylate inhibitors have been approved for
various therapeu8c indica8ons; however, spirapril has
never been marketed. Lisinopril is chemically unique in two
respects.
•  First, it contains the basic amino acid lysine (R1 =
CH2CH2CH2CH2NH2) instead of the standard nonpolar
alanine (R = CH3) residue
•  Second, it does not require bioac8va8on, because neither
of the carboxylic acid groups are esterified (i.e., R2 = H).
Lisinopril was developed at the same 8me as enalapril.
•  Despite the addi8on of another ionizable group, the oral
absorp8on of lisinopril was found to be superior to that of
enalaprilat but less than that of enalapril.
•  In vitro studies of enalaprilat and lisinopril showed lisinopril
to be slightly more potent than enalaprilat. Lisinopril, along
with captopril, currently are the only two ACE inhibitors
that are not pro-drugs.
•  The major structural difference among the remaining ACE inhibitors
is in the ring of the C-terminal amino acid.
•  Lisinopril, like enalapril and captopril, contains the pyrrolidine ring
of proline, whereas all the other compounds contain larger bicyclic
or spiro ring systems.
•  Studies of indoline analogues of captopril indicated that a
hydrophobic pocket similar to that seen in carboxypep8dase A also
was present in ACE.
•  This led to a modifica8on of Ondel and Cushman's original model
and the development of inhibitors that contained larger
hydrophobic ring systems.
•  Although this modified model was proposed for captopril
analogues, it is readily adaptable to include enalaprilat analogues.
•  In general, the varied ring systems seen in benazepril, moexipril,
perindopril, quinapril, ramipril, spirapril, and trandolapril provide
enhanced binding and potency.
•  They also lead to differences in absorp8on, plasma protein binding,
elimina8on, onset of ac8on, dura8on of ac8on, and dosing among
the drugs
Modified model of ACEI binding
 Phosponate-containing Inhibitors: the
development of fisinopril

The interac8on of the zinc atom with the phosphinic acid is

similar to that seen with sulhydryl and carboxylate groups
•  The compound is capable of forming the ionic, hydrogen,
and hydrophobic bonds similar to those seen with
enalapril and other dicarboxylate analogues.
•  A feature unique to this compound is the ability of the
phosphinic acid to more truly mimic the ionized,
tetrahedral intermediate of pep8de hydrolysis.
•  Unlike enalapril and other dicarboxylate analogues,
however, the spacing of this tetrahedral species is
shorter, being only two atoms removed from the proline
nitrogen.
•  Addi8onally, the spacing between the proline nitrogen
and the hydrophobic phenyl ring is one atom longer than
that seen in the dicarboxylates.
•  Structural modifica8on to inves8gate more hydrophobic,
C-terminal ring systems, similar to that described above
for the dicarboxylate compounds, lead to a 4-
cyclohexylproline analogue of the original phosphinic
acid
•  Fosinoprilat was more potent than captopril but
less potent than enalaprilat
•  Differences in the spacing of the phosphinic acid
and phenyl groups may be responsible for this
la\er difference in potency.
•  Similar to the dicarboxylates, fosinoprilat was too
hydrophilic and exhibited poor oral ac8vity. The
pro-drug fosinopril contains an (acyloxy)alkyl
group that allows be\er lipid solubility and
improved bioavailability.
•  Bioac8va8on via esterase ac8vity in the intes8nal
wall and liver produces fosinopril
 Structure-Ac-vity Rela-onship
•  ACE is a stereoselec8ve drug target. Because currently
approved ACE inhibitors act as either di- or tripep8de
substrate analogues, 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.
•  Later work by Patche\ et al. reinforced this idea. They
reported a 100- to 1,000-fold loss in inhibitor ac8vity
whenever the configura8on of either the carboxylate or the
R1 subs8tuent was altered.
•  The S,S,S-configura8on seen in enalapril and other
dicarboxylate inhibitors meets the above-stated criteria
and provides for op8mum enzyme inhibi8on.
 Physicochemical Proper-es
•  Captopril and fosinopril are acidic drugs, but all other ACE inhibitors are
amphoteric. The carboxylic acid a\ached to the N-ring is a common
structural feature in all ACE inhibitors.
•  It has a pKa in the range of 2.5 to 3.5 and will be ionized primarily at
physiological pH
•  The pKa and ioniza8on on the secondary amine in the dicarboxylate
series depend on the weather the adjacent func8onal group is in the
pro-drug or ac8ve form.
•  In the pro-drug form, the amine is adjacent to an ester, is less basic,
and is primarily un-ionized at physiological pH
•  Following bioac8va8on, the amine is adjacent to an ionized carboxylic
acid that enhances both the basicity and ioniza8on 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 a\ached 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, respec8vely. The analogous
values for these func8onal groups in lisinopril are 3.3 and 1.7
•  The calculated log P values along with other pharmacokine8c
parameters for the ACE inhibitors with three notable excep8ons,
captopril, enalaprilat, and lisinopril, all of the compounds possess good
lipid solubility.
•  Compounds that contain hydrophobic bicyclic ring systems are more
lipid soluble than those that contain proline.
•  A comparison of the log P values of benazepril, fosinopril, moexipril,
perindopril, quinapril, ramipril, spiropril, and trandolapril to those for
captopril and enalapril illustrates this fact.
•  As previously discussed, enalaprilat is much more hydrophilic than its
ester pro-drug and is currently the only ACE inhibitor marked for IV
administra8on.
•  In terms of solubility, lisinopril probably is the most interes8ng
compound in that it is the most hydrophilic inhibitor, yet unlike
enalaprilat, it is orally ac8ve.
•  One possible explana8on for this phenomenon is that in the
duodenum, lisinopril will exist as a di-zwi\erion in which the ionized
groups can internally bind to one another. In this manner, lisinopril
may be able to pass through the lipid bilayer with an overall net
neutral charge.
 Metabolism
•  Lisinopril and enalaprilat are excreted unchanged,
whereas all other ACE inhibitors undergo some
degree of metabolic transforma8on.
•  All dicarboxylate and phosphonate pro-drugs must
undergo bioac8va8on via hepa8c esterases.
•  Addi8onally, based on their structural features,
specific compounds can undergo metabolic
inac8va8on via various pathways
•  Because of its sulhydryl group, captopril is subject
to oxida8ve dimeriza8on or conjuga8on.
•  Approximately 40 to 50% of a dose of captopril is
excreted unchanged, whereas the remainder is
excreted as either a disulfide dimer or a captopril-
cysteine disulfide.
•  Glucuronide conjuga8on has been reported for benazepril,
fosinopril, quinapril, and ramipril. This conjuga8on can
occur either with the parent pro-drug or with the ac8vated
drug.
•  Benazepril, with the N-subs8tuted glycine, is especially
suscep8ble to this reac8on because of a difference in steric
hindrance.
•  For all ACE inhibitors, except benazepril, the carbon atom
directly adjacent to the carboxylic acid is part of a ring
system and provides some steric hindrance to conjuga8on.
•  The unsubs8tuted methylene group (i.e., –CH2–) of
benazepril provides less steric hindrance and, thus,
facilitates conjuga8on.
•  Moexipril, perindopril, and ramipril can undergo cycliza8on
to produce diketopiperazines. This cycliza8on can occur
with either the parent or ac8ve forms of the drugs.
 Pharmacokine-c Parameters
•  The oral bioavailability of this class of drugs ranges from 13
to 95%.
•  Differences in both lipid solubility and first-pass
metabolism are most likely responsible for this wide
varia8on. Both parameters should be considered when
comparing any two or more compounds. With the
excep8ons of enalapril and lisinopril, the concurrent
administra8on of food adversely affects the oral absorp8on
of ACE inhibitors.
•  Product literature specifically instructs that captopril
should be taken 1 hour before meals and that moexipril
should be taken in the fas8ng state.
•  Although not specifically stated, similar instruc8ons also
should benefit pa8ents taking an ACE inhibitor whose
absorp8on is affected by food.
•  The extent of protein binding also exhibits wide
variability among the different compounds.
•  The data suggests that this varia8on has some
correla8on with the calculated log P values for the
compounds.
•  Three of the more lipophilic compounds—fosinopril,
quinapril, and benazepril—exhibit protein binding of
greater than 90%, whereas three of the least lipophilic
compounds—lisinopril, enalapril, and captopril—
exhibit much lower protein binding.
•  The lack of a protein binding value for spirapril
prevents a more defini8ve statement on this
correla8on
•  Renal elimina8on is the primary route of elimina8on for most ACE
inhibitors. With the excep8ons of fosinopril and spirapril, altered
renal func8on significantly diminishes the plasma clearance of ACE
inhibitors, including those that are eliminated primarily by the
feces.
•  Therefore, the dosage of most ACE inhibitors should be reduced in
pa8ents with renal impairment.
•  Studies of fosinopril in pa8ents with heart failure demonstrated
that it is eliminated by both renal and hepa8c pathways and does
not require a dosage reduc8on in pa8ents with renal dysfunc8on.
•  Spirapril also exhibits similar proper8es; however, it is not currently
available for use.
•  It should be noted that the literature data for routes of elimina8on
are not always consistent. The designa8on of renal elimina8on is
quite clear, but it is difficult to correlate what some sources call
renal/hepa8c elimina8on with what others call renal/fecal
elimina8on. Addi8onally, it is uncertain whether the designa8on of
fecal elimina8on also includes unabsorbed drug. As a result, there
is some variability for major routes of elimina8on listed in Table
28.3.
•  With one excep8on, all ACE inhibitors have a similar
onset of ac8on, dura8on of ac8on, and dosing interval.
•  Captopril has a more rapid onset of ac8on; however, it
also has a shorter dura8on and requires a more
frequent dosing interval than any of the other
compounds.
•  When oral dosing is inappropriate, enalaprilat can be
used IV.
–  The normal dose administered to hypertensive pa8ents is
0.625 to 1.25 mg every 6 hours
–  The dose usually is administered over 5 minutes and may
be 8trated up to 5 mg IV every 6 hours.