ACE Inhibitors: A Comprehensive Review

Abstract

Hypertension is a chronic increase in blood pressure, characterized as primary and secondary hypertension. The disorder is associated with various risk factors like obesity, diabetes, age, lack of exercise etc. Hypertension is being treated since ancient times by Ayurvedic, Chinese and Unani medicine. Now various allopathic drugs are available which include diuretics, calcium channel blockers, α-blockers, β-blockers, vasodilators, central sympatholytics and ACE-inhibitors. Non-pharmacological treatments include weight reduction, dietary sodium reduction, increased potassium intake and reduction in alcohol consumption. ACE-inhibitors are widely used in the treatment of hypertension by inhibiting the angiotensin converting enzyme responsible for the conversion of angiotensin I to angiotensin II (responsible for vasoconstriction). Various structure activity relationship studies led to the synthesis of ACE-inhibitors, some are under clinical development. This comprehensive review gives various guidelines on classification of hypertension, hypertension therapy including ancient, pharmacological, non-pharmacological therapies, pharmacoeconomics, historical perspectives of ACE, renin, renin angiotensin system (circulating vs local RAS), mechanism of ACE inhibitors, and development of ACE inhibitors. Review also emphasizes on the recent advancements on ACE inhibitors including drugs in clinical trials, computational studies on ACE-inhibitors, peptidomimetics, dual, natural, multi-functional ACE inhibitors, and conformational requirements for ACE-inhibitors. HYPERTENSION: Hypertension is a chronic increase in arterial blood pressure. In general if the diastolic blood pressure is more than 80 mm/Hg and systolic blood pressure more than 120 mm/Hg the person is said to be hypertensive 1 . The Natural history of hypertension was first reported by Frederick Mahomed (1849-1884) 2 . Hypertension is categorized primarily two types viz primary hypertension and secondary hypertension.

Full text

Arora and Chauhan, IJPSR, 2013; Vol. 4(2): 532-548 ISSN: 0975-8232
Available online on www.ijpsr.com 532
IJPSR (2013), Vol. 4, Issue 2 (Review Article)
Received on 30 September, 2012; received in revised form, 06 December, 2012; accepted, 18 January, 2013
ACE INHIBITORS: A COMPREHENSIVE REVIEW
Pradeep Kumar Arora* and Ashish Chauhan
Department of Pharmacy, Lovely Professional University, Phagwara, Punjab, India
ABSTRACT
Hypertension is a chronic increase in blood pressure, characterized as
primary and secondary hypertension. The disorder is associated with various
risk factors like obesity, diabetes, age, lack of exercise etc. Hypertension is
being treated since ancient times by Ayurvedic, Chinese and Unani medicine.
Now various allopathic drugs are available which include diuretics, calcium
channel blockers, α-blockers, β-blockers, vasodilators, central sympatholytics
and ACE-inhibitors. Non-pharmacological treatments include weight
reduction, dietary sodium reduction, increased potassium intake and
reduction in alcohol consumption. ACE-inhibitors are widely used in the
treatment of hypertension by inhibiting the angiotensin converting enzyme
responsible for the conversion of angiotensin I to angiotensin II (responsible
for vasoconstriction). Various structure activity relationship studies led to the
synthesis of ACE-inhibitors, some are under clinical development. This
comprehensive review gives various guidelines on classification of
hypertension, hypertension therapy including ancient, pharmacological, non-
pharmacological therapies, pharmacoeconomics, historical perspectives of
ACE, renin, renin angiotensin system (circulating vs local RAS), mechanism of
ACE inhibitors, and development of ACE inhibitors. Review also emphasizes
on the recent advancements on ACE inhibitors including drugs in clinical
trials, computational studies on ACE-inhibitors, peptidomimetics, dual,
natural, multi-functional ACE inhibitors, and conformational requirements for
ACE-inhibitors.
HYPERTENSION: Hypertension is a chronic increase in
arterial blood pressure. In general if the diastolic blood
pressure is more than 80 mm/Hg and systolic blood
pressure more than 120 mm/Hg the person is said to
be hypertensive
1
. The Natural history of hypertension
was first reported by Frederick Mahomed (1849-1884)
2
.
Hypertension is categorized primarily two types viz
primary hypertension and secondary hypertension.
Primary Hypertension: Primary hypertension also
known as essential hypertension which is a
heterogeneous disorder having different causal factors
in different patients that lead to high blood pressure. It
may be due to stress, high fat, high sodium diet,
secondary causes such as renovascular disease, renal
failure, pheochromocytoma, aldosteronism or other
causes of hypertension are not present. It includes
total of 95% of all cases of hypertension
3-4
.
Secondary Hypertension: This is the condition of
hypertension, secondary to some disorders such as
renal parenchymal diseases or with disorders like
pheochromocytoma, cushing’s syndrome (elevated
adrenal activity), primary aldosteronism, myxoedema,
renal vascular disorders etc.
5
.
Keywords:
Hypertension, Blood pressure, Global
market, Clinical trials, Recent
advancements, Pharmaco-economics
Correspondence to Author:
P.K. Arora
Department of Pharmacy, Lovely
Professional University, Phagwara,
Punjab, India
E-mail: pradeeparora50@gmail.com
ABBREVIATIONS:
CAGR- Compound annual growth rate,
ACE- Angiotensin converting enzyme,
RAS- Renin angiotensin system,
KKS- Kallikrien system,
PCPA- Pancreatic carboxypeptidase A,
ESH- European society of hypertension,
JNC- Joint national committee,
WHO- World Health Organization,
SGO- Silicon graphics workstation,
PET- Positron emission tomography,
GPI- Glycosyl phosphatidyl inositol,
NEP- Neural endopeptidases,
COS- Chitooligosaccharides

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Guidelines of Hypertension
6-7
: The hypertension is
classified in accordance to ESH, JNC and WHO is listed
in Table 1.
Etiology: Obesity, diabetes, age, race-african,
americans have higher risk than caucasians, family
history of high blood pressure, high normal blood
pressure, high salt diet, high saturated fat diet, lack of
exercise, poor physical fitness, alcoholism, stress,
inactivity
8
. The pathophysiology of hypertension is
shown in figure 1.
TABLE 1: GUIDELINES OF HYPERTENSION
GUIDELINES
ESH
27
JNC
28
WHO
28
TYPE
SYS.
DIAS.
SYS.
DIAS.
SYS.
DIAS.
Optimal
<120
<80
-
-
<120
<80
Normal optimal
120-129
80-84
<120
<80
120-129
80-84
High normal
130-139
85-89
130-139
85-89
130-139
85-89
Stage-1 Mild hypertension
140-159
90-99
140-159
90-99
140-159
90-99
Sub group borderline
-
-
-
-
140-159
90-94
Stage-2 Moderate hypertension
160-179
100-109
160-179
100-109
160-179
100-109
Stage-3 Severe hypertension
≥180
≥110
≥180
≥110
≥180
≥110
Isolated hypertension
≥140
<90
-
-
≥140
<90
Sub group border line
-
-
-
-
140-149
<90
FIGURE 1: PATHOPHYSIOLOGY OF HYPERTENSION

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Types of treatments available: Various types of
treatments are available for hypertension:
1) Allopathic treatment
2) Ayurvedic treatment
3) Chinese treatment
4) Unani treatment
Allopathic treatment: Allopathic treatment includes
various drugs belonging to different classes such as
angiotensin converting enzyme (ACE) inhibitors,
angiotensin receptor blockers, diuretics, calcium
channel blockers, α-blockers, β-blockers, vasodilators,
central sympatholytics
9
.
Ayurvedic treatment: Various herbs reported in
Ayurveda are also used for the treatment of
hypertension since ancient times. Primarily herbs used
for hypertension were; Rauwolffia serpentina
(Reserpine (1)), Ocimum gratissimum (α-Pinene (2),
Camphene (3), Myrcene (4)), Pluchea lanceolata
(Quercetin (5)), Terminalia chebula (Chebulic acid (6))
10
. Some remedies in Ayurvedic medicine are as
follows:
1) Including hot spices like mustard and onion in the
diet.
2) Taking crushed garlic, clove with honey once or
twice a week.
3) Nutmeg powder is taken with warm milk.
4) Mixture of valerian (1 part), gotu kola (1part),
and 1-3g of ashwagandha taken with warm water
or with ghee.
5) Other herbals include calamus, valerian, skullcap,
jatamansi, black pepper, myrrh, hawthorn,
berries, berryberry and cardamom used in
hypertension
11
.
Chinese treatment: The regimen used in chinese
medicine includes tetrandra root (Radix Stepphaniae
tetrandrae), Eucommia bark (Cortex eucommiae),
prunella/self-heal spike (Spica prunellae), Chinese
angelica root (Radix angelica sinensis) and earthworm
(Lumbricus)
12
.
Unani treatment: Different types of khamira are used
for the treatment of various types of cardiovascular
disorders, in particular khamira marwareed is used for
hypertension. It consists of four constituents from
plant origin and two constituents of animal origin
13
.
The composition is given in Table 2.
TABLE 2: COMPOSITION OF KHAMIRA MARWAREED
INGREDIENTS
Qty.
Marwareed (Mytilus margaritiferus)
25g
Tabasheer (Bambusa arundinaceae)
25g
Sandal safaid (Santalum album)
25g
Ambar (Ambra grasea)
10g
Arq-e-gulab (Rosa damascene)
1Lt
Ark-e-baidmusk (Salix caprea)
1Lt
Quaind safaid
1.2Kg
Non-pharmacological treatment: Non pharmacological
treatment include life style modifications, weight
reduction, dietary sodium reduction and increase
potassium intake, physical activity, reduction in alcohol
consumption, a diet consist of fruits, vegetables and
reduced saturated fat is suitable for the hypertensive
patients. It leads to attenuate the risk of cardiovascular
diseases, renal failure etc.
14
.
Global Market: The share of antihypertensive drugs in
the global market is $36.9 billion in 2009 with
compound annual growth rate (CAGR) of 5.3% from
2001 to 2009.

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The market is forecast to decline at a CAGR of -5.5%
between 2009 and 2016 due to expiration of patent of
some drugs
15
. The average daily cost for the
consumption of antihypertensive drugs per class of
medication ranges from 0.19 Ɛ for the diuretics to 0.56
Ɛ for ACE inhibitors in Germany
16
.
Global market data reveals that currently there is very
strong competition in the antihypertensive market. In
2009 angiotensin receptor blockers such as DIOVAN®,
ATACAND®, BIOPRESS®, AVAPRO® were dominant
among all the antihypertensives used. A total of 60% of
global antihypertensive market was dominated by
agents acting on renin angiotensin system among them
angiotensin receptor blocker alone accounted for
42.6%. The second most prescribed antihypertensive
drugs are β-blockers account for approximately 30% of
the global antihypertensive prescription volume and
the third leading therapeutic class of antihypertensives
is diuretics which accounts for 17% of the total
antihypertensive prescription.
Diuretics are the most cost effective drugs and are less
prescribed as compared to angiotensin receptor
blocker and ACE inhibitors. In 2009 diuretics covered
30-40% of the global antihypertensive market
17
.
Angiotensin Converting Enzyme (ACE) Inhibitors: ACE
inhibitors are the drugs which lowers the increased
blood pressure by inhibiting the angiotensin converting
enzyme responsible for the conversion of angiotensin I
to angiotensin II. Angiotensin II is a vasoconstrictor
causes to increase in blood pressure. ACE inhibitors
prevent the progression of renal disease by causing a
reduction in angiotensin II mediated intraglomerular
pressure
18
.
Therapeutic dimensions of ACE inhibitors: In 1970s,
the interruption of Renin Angiotensin System (RAS) by
pharmacological therapy was considered beneficial for
patients with high renin hypertension due to lowering
of increased blood pressure. This has led to the
development of ACE inhibitors. Presently ACE
inhibitors have significant role in the treatment of
myocardial infarction, hypertension, diabetic and
diabetic complications. These drugs can be combined
safely with angiotensin receptor blockers, calcium
channel blockers and thiazide diuretics with varying
degree of beneficial effects
19
.
The renin angiotensin system and the kallikrein system
(KKS) originated in late 19th century. Skeggs et al.
reported that in horse plasma renin liberates a
decapeptide called angiotonin now called angiotensin I
which is converted to angiotensin II in the presence of
chloride ions by a factor which was later named
angiotensin converting enzyme
20
.
Studies of substrate and inhibitors of ACE show that
ACE peptidase is a similar carboxypeptidase to
pancreatic carboxypeptidase A (PCPA). Pancreatic
carboxypeptidase A has two binding sites a zinc binding
site and a cationic binding site. On the basis of this
study ACE also have those two important binding sites
although some other auxiliary binding sites may also
exist
21
.
Renin: Lumbers in 1971 reported that amniotic fluid at
low pH in cold has renin activity. Renin is an enzyme
comes under aspartic proteases. Renin shows
remarkable specificity for its only substrate angio-
tensinogen due to monospecific nature
22
. The primary
structure of renin precursor consist of 406 amino acids
with a pre and pro segment carrying 20 and 46 amino
acids respectively mature renin contains 340 amino
acids and has a mass of 37kDa
23
. Renin includes two
homologous lobes where the active site is present in
the deep cleft located between the two lobes.
Seven amino acids units of the substrate (angio-
tensinogen) are accommodated in the active site.
Renin cleaves the Leu-Val peptide bond with in
substrate to form angiotensin-I. Renin is produced
from an enzymatically inactive precursor prorenin after
activation; activation of prorenin can be achieved by
proteolytic and non- proteolytic. Proteolytic activation
occurs in juxtaglomerular (J.G.) cells of kidney includes
removal of pro-peptide chain
24-25
.
Angiotensin Converting Enzyme: ACE is found in the
microvillar structure of proximal tubules and also of
small intestine placenta and choroids plexus in higher
concentration
20
. It is a dipeptidylpeptidase trans
membrane bound enzyme originally isolated from
horse blood
26
. Proteolytic cleavage of its COOH-
terminal leads to the soluble form of angiotensin
converting enzyme in membrane bound form. ACE
exists in two distinct forms testicular and somatic.

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Both these forms are transcribed from a single gene
but at different initiation sites. Testicular form of ACE is
a protein (100-110 kDa) having a single catalytic
domain corresponding to similar COOH-terminal of
somatic ACE. Somatic form is a protein (150-180 kDa)
synthesized by the vascular endothelium and by
several neural and epithelial cell types having two
identical catalytic domains and a cytoplasm tail
27-28
.
Renin Angiotensin System: Pathogenesis of hyper-
tension depends on the renin angiotensin system.
Angiotensin II is the final product of this pathway. The
whole cascade begins with renin (figure 2).
FIGURE 2: PHYSIOLOGICAL REGULATION OF ELECTROLYTE BALANCE, PLASMA VOLUME AND BLOOD PRESSURE BY THE RENIN
ANGIOTENSIN SYSTEM
30-31
Angiotensinogen is cleaved by renin into angiotensin I
(Ang I). This is further acted by the angiotensin
converting enzyme to produce angiotensin II (Ang II).
Angiotensin binds to the different angiotensin-II
receptors AT-1 and AT-2 and shows its different
actions. Both these receptors when activated by angII
show different significant actions.
AT-2 is responsible for most of the physiological
actions like vasodilatation whereas AT-1 receptor
mediate the vasoconstrictive actions. The two subtypes
of angiotensin receptor-1 have been recognized in rat
and mouse AT-1a and AT-1b. In humans AT-1b receptor
is identified, the other two subtypes are found to be
identical but produced from two distinct genes which
are expressed and regulated differently
29
.
Role of AT-1 Receptor: AT-1b receptor is responsible
for dipsogenic response to angiotensin II in the central
nervous system. Whereas vascular tone and sodium
resorption is regulated by AT-1a in periphery it also
regulates pressor responses to angiotensin II in the
CNS. There are two types of renin angiotensin system
found in human circulating and local renin angiotensin
system.
Circulating vs local RAS:
1. Circulating RAS (C-RAS): Circulating renin
angiotensin system is found in plasma and
mediates the action of renin on angiotensinogen
cleavage to angiotensin in plasma via systemic
circulation.

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Renin is originated from kidney and transported to
pulmonary vasculature, angII formed is conveyed
to peripheral tissues via the circulatory system.
2. Local Renin Angiotensin System: Tissue renin
angiotensin system is a local angiotensin
generating system that found in the tissue is
capable of generating action of angII. Tissue RAS is
found in many organs including the heart brain
pancreas kidney adipose tissue gonads
29
.
Classification of ACE inhibitors: The drugs of this class
are divided in to five sub classes as given below:
1. Sulfhydryl (-SH) containing analogs
32
.
2. Carboxyl (-COOH) containing analogs
32
.
3. Phosphoryl (-PO
2
) containing analogs
32
.
4. Hydroxamic non amino acid derivatives
33
.
5. Peptides
34- 36
.
6. Peptidomimetics
37
.
The potency of the drugs depends on the affinity of the
various drugs towards the zinc binding site. The
carboxyl group containing derivatives tends to be most
potent of the five classes. Also the ACE inhibitor
activity also increases with increase in the lipophillicity.
On this basis ACE inhibitors may be broadly categorized
into either tissue affinity or serum-affinity groups.
Structure of Angiotensin Converting Enzyme: X-ray
crystallography studies of angiotensin converting
enzyme and carboxypeptidase A have shown that ACE
has binding site similar to that of pancreatic
carboxypeptidase A and other auxiliary binding site
38
(Fig. 3, 4).
Ferreira et al., in 1965 reported teprotide (7) which is
isolated from venom peptide of Pit viper (Bothrops
jaraca)
39
has the best duration of ACE inhibitory
activity in vivo, the first ACE inhibitor to be studied was
the teprotide, which shows useful blood lowering
activity but its lack of oral activity limited its
therapeutic use. SAR studies using synthetic venom
peptide analogs improved the understanding of active
site of ACE. The optimal carboxy terminal amino acid
sequence of inhibitor for binding to the ACE was Phe-
Ala-Pro.
FIGURE 3: THE KNOWN ACTIVE SITE OF CARBOXYPEPTIDASE A,
AND A HYPOTHETICAL MODEL OF THE ACTIVE SITE OF ACE. Sub
sites S1, S2 and so on are areas or pockets in the structure of each
enzyme that interact with adjacent side-chains of amino-acid
residues of an enzyme-bound peptide substrate. Functional
groups participate in catalysis of peptide bond cleavage. X–H is a
postulated hydrogen bond donor. In the known structure of the
active site of carboxypeptidase A, the carboxylate, phenolic and
positively charged groups are Glu270, Tyr248 and Arg145,
respectively
38
FIGURE 4: PROPOSED ACTIVE SITE BINDING OF ACE BY A VENOM
PEPTIDE INHIBITOR OR BY SUBSTRATE WITH TERMINAL
SEQUENCE PHE–ALA–PRO, BY SUCCINYL AMINO ACIDS, AND BY
CAPTOPRIL
The side chains on these three amino acids were
assumed to interact with sub sites and pockets at the
active site
33
. David and Miguel proposed a new ACE
inhibitor called benzylsuccinic acid (8), which is not a
potent inhibitor of ACE but provide important
breakthrough for the further development of ACE
inhibitors.

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Extensive SAR studies of ACE inhibitors suggested that
2-methylsuccinyl-l-proline (Fig. 5) was optimal for
binding to ACE increase in the length of side chain by
adding another methyl to succinic acid did not enhance
the activity over the succinic acid derivative 2-d-D-
methylglutaryl-L-proline.
FIGURE 5: DESIGN OF CAPTOPRIL
Another modification is the replacement of the
carboxyl group by a mercapto group which led to a
dramatic improvement of the ACE inhibitor activity and
produced the first marketed drug Captopril (IC
50
23nM)
40
. Another sulfhydryl drug is Zofenopril (9) (IC
50
8nM)
which is more potent than Captopril
41
.
ENALAPRIL ANALOGUES GENERAL STRUCTURE
SAR of Enalapril analogs (Table 3):
1. To enhance the potency over the captopril
analogs modifications has been done that leads
to the development of Enalapril (10) with IC
50
5.5nM and its analogs with general structure
(11) (carboxyl group containing).
2. Cyclic amino acids e. g. proline gives better
activity. The cyclic nature of proline provides
steric hindrance to amide bond hydrolysis and
allows for therapeutic utility (Lisinopril).
3. The side chain methyl group is responsible for
the hydrophobic interaction and the carbonyl
oxygen involved in hydrogen bonding.
4. The substitution of amino butyl group in place
of methyl group gives compound with increase
oral bioavailability. e.g. Lisinopril (IC
50
4.7nM)
5. Ring replacement with five or six membered
ring gives new compounds with increased
activity. e.g. Cyclopentane (Ramipril) IC
50
4.0nM.
40
6. Ring replacement with tetrahydroisoquinoline
gives more potent compound than enalapril
e.g. Moexepril (IC
50
2.6nM).
26
7. Ring replacement with indole gives the active
compound Perindopril (IC
50
1.44nM).
42
Various
other carboxyl containing analogs are
Benazepril (12) (IC
50
1.7nM), Cilazapril (13) (IC
50
1.93nM), Delapril (14) (IC
50
40.0nM),
47
Alacepril
(15), Temocapril (16) (IC
50
3.6Nm).
48

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TABLE 3: STRUCTURE ACTIVITY RELATIONSHIP OF ENALAPRIL ANALOGS
DRUG
RING
R
1
R
2
R
3
IC
50
Lisinopril
42
N
COOH
(CH
2
)
4
NH
2
H
4.7nM
Pirindopril
42
N
H
H
COOH
CH
3
CH
2
CH
3
CH
3
1.44nM
Ramipril
42
N
HH
COOH
CH
3
CH
2
CH
3
4.0nM
Spirapril
42
N
S
S
HOOC
CH
3
CH
2
CH
3
16µg
Moexepril
42, 43
N
OCH
3
OCH
3
HOOC
CH
3
CH
2
CH
3
2.6nM
Quinapril
44, 45
N
HOOC
CH
3
CH
2
CH
3
8.3nM
Trandolapril
46
N
HH
COOH
CH
3
CH
2
CH
3
0.9nM
Phosphoryl containing Analogs: In phosphorous
containing analogs, the zinc binding site groups has
been replaced with phosphorous containing groups i.e.
Phosphinyl group (O=P-OH). The optimal distance is
maintained to both the cationic site with the carboxyl
group of proline and with the anionic hydroxyl of the
phosphinyl group (O=P-OH) to the zinc binding site.

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The size of the phosphorous atom is critical for
maintaining the appropriate distance
40
e.g. Fosinopril
(17), [[Hydroxy(4-phenylbutyl)phosphinyl]acetyl]-L-
proline (18).
Hydroxamic Non Amino Acid Derivatives: Idrapril (19)
is a prototype drug of this novel class of ACE inhibitors
consists of non peptidomimetic structure with a
hydroxamic group and having a similar pharmaco-
logical profile to Captopril. It shows short elimination
half-life of 2 hours and has a much longer effect on RAS
and blood pressure (12-24 hrs), without affecting heart
rate
49
.
Other ACE inhibitors:
1. RXPA 380: RXPA 380 (20) is a testis ACE inhibitor.
The conformation in the central backbone is much
similar to the captopril than enalapril. The RXPA
380 compound occupies more active sub sites of
the testis ACE than the previously determined
inhibitor ACE inhibitor complexes and possess the
bulkier moieties that extend in to the S
2
and S
2
50
.
2. RXPA 407: RXPA 407 (21) is new synthetic
phosphine peptides which have been tested for
their ability to inhibit ACE exhibiting remarkable
preference for only N-domain. RXPA 380 inhibit
3000 fold preferentially at the C-domain active site
while the RXPA 407 has 1000 fold higher affinity
for the N-domain active site
51-52
.
(17)
P
N
O
HO
O
COOH
(18)
COOHN
N
H
OH
O
O
H
3
C
(19)
O NH
P
NH
OH
O
O
O
OH
O
(20)
P
H
3
C
HN
CH
3
NH
2
O
H
N
HN
CH
3
O
O
HO
O
OH
O
O
(21)
P
N
HOOC
O
O
O
H
N
O
O CH
3
CH
3
H
3
C
H
3
C
Computational studies of ACE inhibitors: Andrew et
al., in 1985 used classical potential energy calculations
using COMOL program (pairwise summation of
vanderwaal’s interactions between non bonded atoms
together with electrostatic torsional potentials) to find
the conformational analysis of few ACE inhibitors
These calculations define the structurural and
conformational requirements for binding to the active
site of ACE (Table 4) which are useful for the further
designing of ACE inhibitors
53
. Certain other
conformational aspects for the ACE inhibitors is
described by E D Thorsette, a series of ACE inhibitors in
which alanylproline of enalapril was replaced by
monocyclic lactam rings.
Molecular mechanics was used for investigations of
model lactams. A correlation was established between
inhibitor potency and computed angles (ψ) for the
lowest energy conformations of model compounds.
The compounds (22-26), show good correlation of ring
size with IC
50
(table 5). More polar isomer II shows
maximum inhibitory potency for the 6-7 member rings
54
.

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TABLE 4: STRUCTURE ACTIVITIES AND CONFORMATIONAL VARIABLES OF ACE INHIBITORS STUDIED
Z
Y X C
H
R
1
C N
O
C
H
R
2
C OH
R
3
O
COMPOUND
Z
Y
X
R
1
R
2
or R
3
IC
50
(M)
Captopril
_
_
CH
2
SH
CH
3
2x10
-8
5-Oxocaptopril
_
_
CH
2
SH
CH
3
O
9x10
-9
SA446
_
_
CH
2
SH
H
S
OH
6.5x10
-8
WY44221
_
_
CH
2
SH
CH
3
3.7x10
-9
A
_
P
O
O
O
H
N
CH
3
1.4x10
-9
MK422
H
2
C
H
2
C
H
2
C
C CO
2
H
N
CH
3
1.2x10
-9
B
H
2
C
H
2
C
P O
O
H
N
CH
3
0.5x10
-9
C
C
H
2
C C
HN
O
C
O
H
2
C
H
3.2x10
-9
N
n(H
2
C)
O
NH
2
CH
3
H
N
N
(CH
2
)n
HOOC
O
COOH
(22-26)
(A-E)
n = 1-5
COMPOUND
n
RING SIZE
IC
50
(iso I)
a
IC
50
(iso II)
a
(MODEL)
b
Ψ
CALC
.
Ψ
X-RAY
22
1
5
1.2x10
-5
1.9x10
-5
A
-132
-
23
2
6
4.3x10
-7
1.7x10
-6
B
-138
-
24
3
7
7.0x10
-7
1.9x10
-8
C
166
166
25
4
8
1.7x10
-6
4.8x10
-9
D
145
159
25 (S,S)
4
8
-
2.0x10
-9
-
-
-
25 (R,R)
4
8
-
9.2x10
-8
-
-
-
26
5
9
1.3x10
-6
8.1x10
-9
E
135
-
ENALAPRIL
-
-
1.2x10
-9
-
140
143
a
IC
50
conc. In molar. Iso. I is the first diester isomer to elute from silica gel and II is the second model lactam is used to obtain Ψ
calc

Arora and Chauhan, IJPSR, 2013; Vol. 4(2): 532-548 ISSN: 0975-8232
Available online on www.ijpsr.com 542
Molecular modeling study revealed that hydrophobic
and hydrogen bonding interactions with residue of C-
domain of S
2
subsite are found to be important for ACE
inhibition activity. X-ray crystal structure of testes ACE
complex with inhibitor of Lisinopril and homology
model structure of N-domain were considered first.
Molecular docking calculations were performed using
DISCOVER module of INSIGHT II on a silicon graphics
octane 1 (SGO-1) workstation. Few compounds were
synthesized and bio evaluated one of the compound
(27a) shows excellent selectivity over N/C-domain. The
P
2
’
tryptophan moieties of compounds (27a) and (27b)
demonstrated additional hydrophobic and hydrogen
bonding interactions with S
2
׳
residues Thr282,Val379,
Val380 and Asp453 of the C-domain active site and
may thus explain the increased C-domain selectivity of
these compounds as compared with lisinopril.
Docking experiments reveals that the potential energy
of the complex of compound (27a) with C-domain is far
better than N-domain. This is in agreement with the
observed biological inhibiting binding affinity i.e.
selectivity of compound (27a)
55
. Another group of
scientist considered isosteric replacement of
carboxylate with phosphate functional group. Carbon
phosphorous bonds were more stable and resist
hydrolytic cleavage. K-26 (28) a phosphonotripeptide is
an α-amino phosphonic acid analogue of tyrosine with
IC
50
value of 4.4nM. Eight analogues were synthesized
and bio evaluated. Replacing the phosphonic acid
group with carboxylic analogue leads to 1500 fold
increase in activity
56
.
A new validated ACE inhibitors pharmacophore
hypothesis developed from the biologically active
(frozen) conformation of Lisinopril-Human ACE
complex using stepwise technique of CATALYST
module. This module was used to design a series of
new 3-mercapto-2-methyl-propanoyl-pyrrolidine
derivatives. Introduction of mercapto functional group,
p-methoxybenzyl moiety and substituted imino
functional group on to the pyrrolidine ring system gives
essential lipophilic pharmacophore to the compounds,
in addition to these functional groups like H-bond
acceptors, hydrophobic features and negative
ionization potential were used as chemical features.
Ph
N
H
H
N
NH
COOH
O
COOH
NH
2
N
H
H
N
NH
COOH
O
COOH
NH
2
Ph
(27a)
(27b)
H
3
C
H
N
N
H
H
N
P
OH
O
CH
3
CH
3
OH
O
O
OH
OH
O
(28)
Molecular simulation studies shows that the
pyrrolidine derivatives have tendency to inhibit ACE,
therefore considered as active antihypertensive hits.
On these basis best pyrrolidine derivatives like (29-32)
were selected as hit compounds for ACE inhibition
57
.
Peptidomimics approaches has been used to discover
new ACE inhibitor in the recent past, several groups
across the globe have tried different types of peptides,
consisting of non peptides moieties like unnatural
amino acids or carboxylic acid derived heterocyclics
conjugated with peptide moiety. Peptides containing
particularly proline
58
, have better bioavailability as
they resist to proteolysis by digestive enzymes
59
. Two
sets of libraries containing lysine and ornithine with
proline as a common moiety were designed and
synthesized in the designing of dipeptide motif, usual
amino acid that is, proline is put at P
2
׳
position. While
P
1
׳
position is occupied by usual (e.g. lysine) or unusual
(e.g. ornithine) amino acids at the P
2
׳
position, the –
COO
-
group of proline is likely to interact with a
positively charged side chain of arginine (or lysine) in
the S
2
׳
subsite of ACE. The S
1
׳
subsite being
hydrophobic in nature, preferentially accepts linear
amino acids like lysine or ornithine for better
interaction at the position P
1
׳
unnamed amino acids
and carboxylic acid derived heterocyclic moieties are
incorporated to interact with S
1
subsite and Zn
2+
ion
located in the enzymes active site. ACE inhibiting
potency of three peptidomimics N-methyl-L-try-
tophan-orn-pro (33), 5-hydroxy-L-tryptophan-orn-pro

Arora and Chauhan, IJPSR, 2013; Vol. 4(2): 532-548 ISSN: 0975-8232
Available online on www.ijpsr.com 543
(34), 2-benzimidazolepropionic acid-orn-pro (35) and
containing heterocyclic moiety was found significant
with IC
50
values 6 x 10
-7
, 4 x 10
-6
and 10 x 10
-6
M
respectively
37
. The result of this study indicates that
the ornithine has important role in tripeptidomimics to
effectively inhibit the ACE activity.
BINDING INTERACTION OF TRIPEPTIDOMIMETIC TO THE ACTIVE
SITE OF ACE
Drugs In Clinical Trials (Table 6): Teprotide (7) a
nonapeptide is the first ACE inhibitor isolated from
viper venom rejected in clinical trial due to lack of oral
bioavailability
39
. Thiorphan enantiomers (36) [IC
50
(R)
860nM, IC
50
(S) 140nM] are dual inhibitors of ACE and
Neuroendopeptidases (NEP). SCH39370 (37) is an ACE
inhibitor has (IC
50
>1000nM). UK-69578 (38)
(Candoxatrilat) with (IC
50
28nM) has discontinued from
phase III clinical trials.
Fasidotril (39) is a dual inhibitor of ACE while its
metabolite Fasidotrilat in phase III clinical trials is a
potent inhibitor of ACE (K
i
= 9.8nM) and NEP (K
i
=
5.6nM) derived through modification of thiorphan (36),
Omapatrilat (40) having IC
50
5nM and 8nM for ACE and
NEP activity. Omapatrilat and Sampatrilat (41) are in
phase III and phase II clinical trials respectively.
Another ACE inhibitor CGS 30440 (42) in clinical trials
have (IC
50
12nM) for ACE and (IC
50
63nM) for NEP
60
.
TABLE 6: COMPOUNDS IN DIFFERENT PHASES OF CLINICAL TRIALS
COMPOUND
STRUCTURE
IC
50
(nM)
COMPANY
STATUS
ACE
NEP
Sampatrilat
OH
OH
H
N
O
HO
O
HN
H
2
N
NH
S
O
O
H
3
C
1.2
8
Pfizer
Halted in Phase II
Omapatrilat
HN
N
S
HS
O
O
OH
O
H
5
8
Bristol-Myers
Squibb
Failed in Phase III
Gemopatrilat
N
H
3
C
H
3
C
OH
O
O
N
H
O
SH
3.6
305
Bristol-Myers
Squibb
Preclinical

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Mixanpril (S21402)
HN
HOOC
CH
3
O
O
CH
3
4.5
1.7
_
Preclinical
Fasidotrilat
HS NH OH
O
O
OH
3
C
9.8
5.6
Eli Lilly
Phase II
CGS30440
H
3
C
NH
HN
O
CH
3
O
O
H
3
C
CH
3
O
O
OCH
3
19
2
_
Preclinical
Recent Advancements: Kondoh et al., proposed that a
novel glycosyl phosphatidyl- inositol (GPI)-anchored
protein releasing activity of ACE by cleaving mannose-
mannose linkage site. Tightly bound ACE inhibitors
weakly inhibit the GPIase activity and not inactivated
by substituting the core amino acid residue necessary
for peptidase activity. Ignacio’s studies suggested that
neither of the both peptidase catalytic domains of ACE
GPIase activity therefore in addition to its classical
catalytic domain ACE may have other novel active
catalytic domain
25
.
Dual Inhibitors of ACE and Neural Endo Peptidase
(NEP): Neural endopeptidase (NEP) is a zinc
metalloproteinase which is very much similar to ACE,
responsible for the degradation of angiotensin-I,
bradykinin and various natriuretic peptides. Therefore,
simultaneous potentiation of atrial natriuretic peptide
via NEP inhibition and attenuation of angiotensin II via
ACE inhibition leads to complementary effects in the
control of hypertension and congestive heart failure
(CHF)
51, 61
.
Omapatrilat: One of the most advanced
peptidomimetic of dual ACE/NEP inhibitors in
development, a bicyclic thiazepinone analogue.
Additional testing has been requested by FDA due to
increasing angioedema
51, 61
.
Various dual ACE/NEP
inhibitors are Fasidotrilat (43) and Sampatrilat.
Chalcones and Heterocyclics: A chalcone, 3-(3-amino-
4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl-prop-2-
en-1-one (44) (IC
50
0.219mM) and a pyrazole
derivative 4,5-dihydro-5-(4-methoxy-3-nitrophenyl)-3-
(3,4,5-trimethoxyphenyl)-1-methyl-1H-pyrazole. (45)
(IC
50
0.213mM) have been designed and synthesized.
IC
50
values shows that the following two compounds
have promising ACE inhibitor activity
62
.

Arora and Chauhan, IJPSR, 2013; Vol. 4(2): 532-548 ISSN: 0975-8232
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ACE inhibitors derived from plants: Kaempferol-3-o-β-
galactopyranoside, a flavanoid isolated from Ailanthus
excelsa of family simaroubiaceae with IC
50
value
260µM
63
.
ACE inhibitors derived from Marine sources: There are
various structurally diverse bioactive compounds
derived from marine resources like chitooligo-
saccharides derivatives (COS) and phlorotannins have
potent ACE inhibitory activity
64
.
The aminoethyl
derivative of chitooligosaccharide (AE-COS) have IC
50
value 0.8017 µg/ml
65
.
Bioactive Peptides: Chitin is a glycan of β (1→4) linked
N-acetyl glucosamine units, widely distributed in
protective exoskeleton of crustaceans and insects.
Chitooligisaccharides such as hetero chitooligo-
saccharides, amino ethyl chitooligo-saccharides, chitin
derivatives chitosan trimer oligomers and carboxylated
chitooligosaccharides have been reported as
possessing potent ACE inhibitor activity
66
.
Phlorotannin: Phlorotannins are the phenolic
compounds which are formed by the polymerization of
phloroglucinol or called as 1, 3, 5-trihydroxybenzene
monomer units
67
.
The IC
50
value of Phlorofucofuroeckol
A (Phlorotannin) is 12.74µM, obtained from marine
brown and red algae
68
.
ACE inhibitory peptides: (Table 7)
TABLE 7: ACE INHIBITORY PEPTIDES
PEPTIDES
IC
50
Arg-Val-Pro-Ser-Leu (46)
20µM
Val-Tyr-Ala-Pro (47)
6.1µM
Val-Ile-Ile-Phe (48)
8.7µM
Met-Ala-Trp (49)
16.32µM
Ala-Val-Phe (50)
-
Ala-Gln-Gly-Glu-Arg-His-Arg (51)
47.01µg/ml
Leu-Gly-Pro (52)
0.72µM
Ala-Gly-Ser (53)
0.13±0.03mg/ml
Phe-Ala (54)
-
Leu-Arg-Pro-Val-Ala-Ala (55)
4.14µM
Ile-Pro-Pro (56)
-
Val-Pro-Pro (57)
-
Val-Glu-Cys-Tyr-Gly-Pro-Asn-Arg-Pro-
Gln-Phe (58)
29.6µM
Met-Ile-Phe-Pro-Gly-Ala-Gly-Gly-Pro-
Glu-Leu (59)
28.7µg/ml
Ala-Leu-Pro-Met-His-Ile-Arg (60)
77-1062µM
A new angiotensin inhibitory peptide has been isolated
from egg white protein hydrolysates. The IC
50
value of
the isolated peptide RVPSL (Arg-Val-Pro-Ser-Leu) (46)
was 20µM. On the basis of remarkable ACE inhibitory
activity, RVPSL may have potential to develop as
nutraceutical with hypertension lowering activity
79
.
Novel peptides with angiotensin converting enzyme
inhibitory activity were isolated from muscle of cuttle
fish (Sepia officinalis). The IC
50
value of three peptides
Val-Tyr-Ala-Pro (47), Val-lle-lle-Phe (48) and Met-Ala-
Trp (49) are 6.1, 8.7 and 16.32 µM respectively. It is
found that all three peptides act as non-competitive
ACE inhibitors
34
. A tripeptide Ala-Val-Phe (50) was
recently purified from insect protein (Spodoptera
littoralis, Lepidoptera) shows promising ACE inhibitory
activity
35
. Bioactive peptide (IKP) derived from arachin
show selective ACE inhibitory activity with competitive
inhibition activity. The observed IC
50
value is obtained
as 7.0 ±1 µM
36
. Peptide extracted from fresh water
zooplankton (Brachionus calyciflonus) was screened for
ACE inhibitory activity with IC
50
47.01 µg/ml.

Arora and Chauhan, IJPSR, 2013; Vol. 4(2): 532-548 ISSN: 0975-8232
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The peptide is seven amino acid sequenced as Ala-Gln-
Gly-Glu-Arg-His-Arg (51) is competitive inhibitor
70
.
A
tripeptide Leu-Gly-Pro (52) Purified from Alaskan
Pollack skin gelatin hydrolysate has IC
50
0.72µM shows
potent activity as ACE inhibitor
71
. A tripeptide isolated
from smooth hound protein hydrolysates (SHPH) or
mustelus mustelus and bovine trypsin with IC
50
0.13±0.03 mg/ml and amino acid sequence Ala-Gly-Ser
(53) has ACE inhibitory activity
72
. Peptide coded DPC
614 obtained from bovine sodium caseinate
fermentate obtained by Lactobacillus of small intestine
of porcine has IC
50
0.8 mg/ml shows ACE inhibitor
activity.
73
Peptide Phe-Ala (54) incorporated with silanediol
group has been synthesized and screened, shows very
low IC
50
value for ACE inhibition
74
. Peptide with
sequence Leu-Arg-Pro-Val-Ala-Ala (55) was isolated
from bovine lactoferrin hydrolysates with IC
50
4.14µM
is non-competitive inhibitor of ACE
75, 76
.
Sour milk
protein Ile-Pro-Pro (56) and Val-Pro-Pro (57) was
evaluated for ACE inhibitory activity in hypertensive
rats and found promising results
77
.
A hendeca peptide isolated from algae (Chlorella
vulgaris) protein with sequence Val-Glu-Cys-Tyr-Gly-
Pro-Asn-Arg-Pro-Gln-Phe (58) having IC
50
against ACE is
29.6 µM
78
.
A peptide from yellow fin sole (Limanda
aspera) from an industrial waste is isolated and
sequenced as Met-Ile-Phe-Pro-Gly-Ala-Gly-Gly-Pro-Glu-
Leu (59) with IC
50
28.7 µg/ml is a non-competitive
inhibitor of ACE
79
.
A peptide from whey protein
sequenced Ala-Leu-Pro-Met-His-Ile-Arg (60) show ACE
inhibitory activity with IC
50
77-1062 µM
80
.
Multifunctional ACE inhibitor: Multifunctional ACE
inhibitors are capable of scavenging reactive oxygen
species (ROS) and superoxide having antioxidant
activity have been synthesized with the following
general formula (61).
R
3
N
R
1
O R
4
OR
5
R
2
(61)
The most potent compound of the series prepared is
N-{2-([1, 2] dithiolan-3-yl) propionyl}-pyrrolidine-2-
carboxylic acid (62) With IC
50
64µM
81
.
Nitro derivatives of ACE inhibitors of general formula:
A-(X
1
-ONO
2
)
S
shows pharmacological activities like
cardiovascular, renal and anti-inflammatory. One of
the potent derivative is N-[(1S)-1-(ethoxycarbonyl)-3-
phenylpropyl]-L-alanyl-L-proline-3-nitroxypropyl ester
hydrogen maleate (63) is having IC
50
30.9±8.4µM
82
.
Bezencon et al., proposed novel tropane derivatives as
ACE inhibitors with general formula (64). The
synthesized and screened tropane derivatives also
show activity against malaria and inhibit aspartyl
proteases secreted by Candida albicans and therefore
act as antifungal. Where W is six membered, non
benzofused, phenyl or heteroaryl ring , substituted via
V in meta or para position.V designated a bond –(CH
2
)
r
-
A-(CH
2
)
s
-, A-(CH
2
)
v
-B- etc. A and B represent -O-, -S-, -
SO-, -SO
2
-, U represent heteroaryl or aryl, T is -CONR
1
-,
R
1
= H, lower alkyl, lower alkenyl, lower alkinyl,
cycloalkyl, aryl, cycloalkyl-loweralkyl. Q is methylene,
M is aryl or heteroaryl, r is 3, 4, 5 or 6, s is 2, 3, 4, 5
83
.
HN
T
Q
M
W
VU
(64)

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Dive et al., proposed ACE inhibitor peptide derivatives
that are N-terminal site selective with amino acid
sequence as follows: Asp-Phe-Ψ (PO
2
CH
2
)-Ala-Xaa
׳
Where Ψ represent that amide bond (-CONH) have
been replaced by phosphonic bond (-CH
2
PO
2
) and Xaa
׳
represent amino acid residue. A peptide with amino
acid sequence as follows: Ac-Asp-Phe-Ψ (PO
2
CH
2
)-Ala-
AlaOH with Ki for N-terminal ACE is 7nM
84
.
Problems associated with Hypertension: The various
problems associated with hypertension are
cardiovascular disease, heart failure, coronary heart
disease, renal insufficiency, peripheral artery disease
and stroke
85
.
A New ACE: A new angiotensin converting enzyme has
been found. This is angiotensin converting enzyme
related carboxypeptidase. It is found that ACE 2 is a
type I integral membrane protein of 805 amino acids.
ACE 2 has been implicated in regulation of heart
function. ACE 2 has catalytic domain which is 42%
identical to that of its closest homolog, somatic ACE.
The human ACE 2 has two domains in its extracellular
region. The first domain is 42% identical to human
somatic ACE and the second domain is present at the
C-terminus and is 48% identical to human collectrin
86
.
Biochemical properties of ACE 2: ACE 2 cleaves a single
peptide from C-terminal residues from a range of
substrate unlike ACE. ACE 2 cleaves decapeptide Ang I
to Ang (1-9) and octapeptide Ang II to Ang (1-7), which
antagonizes the action of Ang II and thus causes
vasodilatation and antiproliferation. Despite of similar
biochemical nature with ACE, ACE 2 is not sensitive to
classical ACE inhibitors
87
.
CONCLUSION: The data compiled in this review may be
very helpful in further studies on ACE inhibitors. The
comprehension in this review enlightens the evolution
of ACE inhibitors, their existence and pipeline drugs of
ACE inhibitors.
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How to cite this article:
Arora PK and Chauhan A: ACE Inhibitors: A Comprehensive Review. Int J Pharm Sci Res. 2013; 4(2); 532-548.