ORIGINAL ARTICLE
A Review of the Structural and Functional Features of
Olmesartan Medoxomil, An Angiotensin Receptor Blocker
David E. Mire, PhD,* Tonous N. Silfani, PhD,† and Michael K. Pugsley, PhD‡
Abstract: The angiotensin II (A-II) type 1 (AT1) receptor–mediated
effects of A-II play a key role in the pathophysiology of hypertension.
Effective inhibition of A-II is provided by the latest class of anti-
hypertensive medications, the AT1 receptor blockers (ARBs). These
orally available agents were developed around a common imidazole-
based structural core. The most recent member of this drug class
to be approved by the Food and Drug Administration, olmesartan
medoxomil, contains unique features that may explain its clinical ef-
ficacy. Key structural elements of olmesartan medoxomil include a
hydroxyalkyl substituent at the imidazole 4-position and a hydrolyz-
able ester group at the imidazole 5-position. Inter- and intramolecular
hydrogen bonding involving these groups may contribute to the po-
tentiation of antagonist activity. After oral administration, olmesartan
medoxomil is deesterified in the intestinal tract to produce the active
metabolite olmesartan, which undergoes no additional metabolic change.
The marked antihypertensive efficacy of olmesartan medoxomil may
result from a unique pharmacological interaction of the drug with the
AT1 receptor, resulting in a potent, long-lasting, dose-dependent
blockade of A-II. This review article characterizes the structural
features of olmesartan that may be responsible for its clinical efficacy.
Inferential pharmacological studies compare and contrast the effects
of olmesartan to those of other ARBs in comparable preclinical
animal models.
Key Words: angiotensin receptor blocker, antihypertensive, chem-
istry, methods, olmesartan medoxomil, structural features
(J Cardiovasc Pharmacol TM 2005;46:585–593)
A ngiotensin II (A-II) type 1 (AT1) receptor antagonists
(ARBs) have become a key component in the antihyperten-
sive armamentarium. Recently reported clinical studies de-
monstrate the important role that this drug class provides in the
treatment of hypertension,1 heart failure,2,3 and renal disease.4
Received for publication March 17, 2005; accepted July 26, 2005.
From the *New Product Planning, Sankyo Pharma Inc, Parsippany, New
Jersey; †Medical and Scientific Affairs, Sankyo Pharma Inc, Parsippany,
New Jersey; and ‡Pharmacology, Forest Research Institute, Jersey City,
New Jersey.
This work was supported by Sankyo Pharma Inc.
Reprints: Michael K. Pugsley, Pharmacology, Forest Research Institute, 19th
Floor, Harborside Financial Center, Jersey City, NJ 07311 (e-mail:
Michael.Pugsley@frx.com).
Copyright Ó 2005 by Lippincott Williams & Wilkins
J Cardiovasc Pharmacol ä  Volume 46, Number 5, November 2005
Although precise mechanisms have not yet been elucidated to
explain all observed clinical benefits, there can be little doubt
that the ability to significantly reduce systolic and diastolic
blood pressure provides much of the benefit seen with ARB
therapy.5 Although this is not the only drug class capable of
producing clinically significant reductions in blood pressure,
the ARBs are unique in their ability to provide such benefit
with a limited side effect profile.6 Interestingly, although blood
pressure lowering occurs by the same mechanism, there are
differences in the antihypertensive efficacy of the various
agents within the ARB class.
The renin–angiotensin–aldosterone system (RAAS) plays
a central role in blood pressure regulation and the pathogenesis
of hypertension. The RAAS consists of an enzymatic cascade.
Angiotensinogen, produced by the liver, is converted to angio-
tensin I (A-I) by renin, which is secreted by juxtaglomerular
cells in the kidneys. Angiotensin-converting enzyme (ACE)
converts A-I to A-II, a powerful peptide hormone responsible
for a myriad of cellular events (Fig. 1).7,8 ACE inhibitors block
the formation of A-II; however, they also prevent the break-
down of bradykinin. The resulting accumulation of bradykinin
as well as substance P and related active peptides may con-
tribute to the development of cough and angioedema, which
are often associated with ACE inhibitor therapy.9,10 Moreover,
ACE inhibition may not completely block the RAAS. In vitro
experiments have shown that angiotensinogen can be converted
to A-II by nonrenin enzymes such as tissue plasminogen acti-
vator, cathepsin G, elastase, and chymostatin, and A-I can be
converted to A-II by non-ACE enzymes such as chymostatin-
sensitive A-II–generating enzyme, chymase, and cathepsin G.9
The primary effector hormone in this system, the octa-
peptide A-II, exerts numerous effects on many different tis-
sues, including vasoconstriction of vascular smooth muscle,
aldosterone secretion from adrenal glomerulosa cells, and tro-
phic changes in the heart and blood vessels via binding with
the AT1 receptor.11
A brief examination of the origin of RAAS-modifying
agents provides a framework for understanding the develop-
ment of olmesartan medoxomil. The first series of com-
pounds that were developed to inhibit the RAAS were
polypeptides that inhibited the action of angiotensin-converting
enzyme (ACE).12 The nonapeptide teprotide was isolated from
the venom of a Brazilian pit viper, Bothrops jararaca, and
served as the first ACE inhibitor to be evaluated.13,14 Teprotide
(SQ 2881) was found to be a highly effective antihypertensive
agent and was devoid of toxicities associated with the pit
viper toxin. However, because of the molecule’s peptidic
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Mire et al J Cardiovasc Pharmacol ä  Volume 46, Number 5, November 2005
FIGURE 1. The antihypertensive mechanism of angiotensin
receptor blockers (ARBs). The diagram depicts the renin–
angiotensin–aldosterone system, in which the renal release of
renin catalyzes the conversion of angiotensinogen (derived
from the liver) to angiotensin I (A-I). A-I is subsequently
converted to angiotensin II (A-II) by circulating and pulmonary
angiotensin-converting enzyme (ACE). A-II produces a multi-
tude of physiological effects, including vasoconstriction,
release of aldosterone from the adrenal cortex, and catechol-
amine release by activating angiotensin (AT1) receptors on
vascular smooth muscle. Olmesartan and related ARBs block
A-II activation of AT1 receptors, providing effective antihyper-
tensive activity. BP indicates blood pressure.7,8
structure, parenteral administration was required, thus limiting
its clinical utility. The antihypertensive effect of teprotide was
shown to result from its ability to inhibit ACE.13 Subsequently,
the first orally active ACE inhibitor, captopril, was developed.15
This prototypical ACE inhibitor was extensively studied and
compared with other efficacious antihypertensive drugs at the
time (including a- and b-adrenergic blockers and peripheral
sympathetic inhibitors such as guanethidine). The use of ACE
inhibitors in hypertensive patient populations resulted in well-
maintained long-term reductions in blood pressure. Additionally,
these compounds demonstrated cardioprotective and renopro-
tective properties, as evidenced by improved survival rates and
end-organ protection not attributable to blood pressure.16
CHEMICAL DEVELOPMENT OF ARBS
There are 2 primary receptors for A-II, denoted AT1
and AT2.17 The binding of A-II to the AT1 receptor mediates
virtually all of the known pathologic effects of A-II that con-
tribute to hypertension. These effects include vasoconstric-
tion, sodium and water retention, and cellular proliferation and
hypertrophy. Activation of the AT2 receptor inhibits gener-
alized cellular proliferation and hypertrophy, thereby antag-
onizing the trophic responses in tissue induced by A-II.7
In vascular endothelial cells, AT2 activation causes dilation of
blood vessels by formation of nitric oxide and bradykinin.17
Although the role of the AT2 receptor is less understood, it
usually exerts opposing effects to the AT1 receptor. Direct
blockade of the site of action of A-II was first explored through
modification of A-II to produce peptide-based antagonists.
586
The peptide antagonists saralasin and sarmesin were
initially synthesized by replacing amino acid residues found
in A-II.18,19 Amino acid modification either reduced or elimi-
nated peptide activity (ie, the ability to activate the AT1 receptor).20
The amino acid sequence of A-II is Asp1-Arg2-Val3-Tyr4-Ile5-
His6-Pro7-Phe8. Replacement of Asp1 with sarcosine, Ile5 with
valine, and Phe8 with alanine resulted in the generation of
saralasin: 1-sarcosine-5-valine-8-alanine angiotensin II or
[Sar1-Val5-Ala8]A-II. Similarly, replacement of Asp1 with
sarcosine and Tyr4 with the methoxy derivative of tyrosine
resulted in production of sarmesin: 1-sarcosine-4-methoxytyr-
osine angiotensin II or Sar-Arg-Val-Tyr(OMe)-Ile-His-Pro-
Phe-OH or [Sar1,Tyr(OMe)4]A-II.20,21
However, despite their efficacy, there were several major
drawbacks associated with this approach to development of
novel antihypertensive drugs. First, these molecules provided
only partial antagonism of the AT1 receptor.22 Second, as
peptides they had little or no oral bioavailability and, like the
first ACE inhibitors, had to be administered parenterally.
Despite these drawbacks, the peptide antagonists provided a
great deal of important mechanistic information regarding the
mode of action of A-II binding to AT1 receptors. Modification
of A-II to produce saralasin and sarmesin uncovered crucial
stereoelectronic (3-dimensional structural and electronic mo-
lecular properties) features of the A-II molecule, notably the
presence of a backbone bend at the Tyr4-Ile5-His6 segment.
The information that resulted showed that to activate the AT1
receptor, the A-II peptide must assume a specific conformation
in which the p-orbitals of the aromatic ring side chains of Tyr4,
His6, and Phe8 overlap.23 This allows the establishment of a
charge-relay system, whereby charge transfer can occur from
the A-II molecule to the AT1 receptor in the form of pro-
tonation (Fig. 2).11 It has been hypothesized that this charge
transfer plays a key role in the activity of A-II on AT1 and the
ensuing conformational change associated with receptor ac-
tivation and subsequent intracellular cascade mechanisms.24
This hypothesis has been validated through the synthesis of
a cyclic analogue of angiotensin II.25 This conformationally
restricted structure confirmed the necessity of a clustered ring
conformation for receptor activation.
The Development and Structure–Activity
Relationship (SAR) of Olmesartan
In the early 1980s, researchers at Takeda Chemical
Industries, Ltd, discovered the first nonpeptide-based A-II
antagonists.26,27 The compounds synthesized were based around
a substituted imidazole core (Fig. 3). The first series of mol-
ecules produced weak (;38%) inhibition of A-II–mediated
contraction of isolated rabbit aortic blood vessels up to
a maximal concentration of 10 mM.26 A second series of
imidazole-5-acetic acid derivatives showed better in vitro
inhibitory actions. These molecules produced 100% inhibi-
tion of A-II in isolated blood vessels at 1-mM concentra-
tions. However, these concentrations resulted in only 40%
to 60% inhibition of an A-II–induced pressor effect in rat
models.27 Although unsuitable as final marketable products
because of low potency and poor oral bioavailability, these
compounds served as useful leads for the development of
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J Cardiovasc Pharmacol ä  Volume 46, Number 5, November 2005
FIGURE 2. A schematic that depicts the putative charge
transfer that occurs from the A-II peptide to the AT1 receptor
(adapted from Moore and Matsoukas11).
subsequent commercially available ARBs. Thus, currently
marketed agents are derived as either N-1 biphenyl analogues
of the original N-1 benzyl Takeda lead compounds or are
derivatives in which thienyl modification has taken place at the
imidazole 5-position of the Takeda lead compounds.28
FIGURE 3. The Takeda lead compound—the first nonpeptide
AT1 blocker.26,27
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Structure and Function of Olmesartan Medoxomil
Many SAR studies examining the imidazole-based
antagonists (ARBs) have been reported and show key elements
required for effective antagonism of AT1, a 7-transmembrane-
spanning G-protein-coupled receptor (GPCR).29–31 The target
sequence for the nonpeptide, imidazole-based antagonists is
the A-II C-terminal pentapeptide Tyr4-Ile5-His6-Pro7-Phe8.31
Analysis of the binding affinity of ARBs to the AT1 receptor
has uncovered a number of common important structural
features. ARB binding involves key acid–base interactions
between acidic moieties of the ARB molecule and basic amino
acid residues on the receptor. Additionally, ARB binding
involves the interaction of hydrophobic substituents with
hydrophobic regions on the receptor, producing weak, but
important, binding forces. Finally, hydrogen bonding between
the ARB and the AT1 receptor is also important for potent
binding affinity.31
Enhancement of binding activity was observed when
a 2#-tetrazole-biphenylmethyl group was introduced at the
imidazole 1-position of the Takeda lead compound. The 2#-
tetrazole-biphenylmethyl group has recently been identified
as a privileged structure. (A privileged structure is a common
molecular framework on which ligands for multiple receptors
can be constructed. This concept has aided in the rational
development of new lead molecules.) This key ligand sub-
structure may increase binding affinity by targeting a conserved
minicore primarily made up of aromatic and nonpolar amino
acid residues within the AT1 receptor.32 The presence of an
acidic group (either a tetrazole or carboxylic acid) at the
2#-position of the biphenyl portion of the molecule provides
for an additional binding position with a basic amino acid group
on, presumably, the highly conserved arginine-167 (Arg167) of
transmembrane region IV of the AT1 receptor.33 Similarly, an
acidic group at the 5-position of the imidazole ring provides
a crucial acidic or hydrogen-bonding point of attachment to the
AT1 receptor.34 The positively charged lysine 199 (Lys199)
residue on transmembrane region V of the AT1 receptor is pro-
posed to be the complementary tight binding site for ARBs.35
It has been proposed that the binding interaction of the
tetrazole might actually be different from the conventional salt
bridge interaction described and may result from an unusual
lysine–aromatic interaction.36 However, studies have shown
that the charge associated with the Lys199 residue is critical for
proper electrostatic interaction of A-II and high binding
affinity36; thus, potent and efficacious antagonists target this
amino acid binding site. In addition, the nitrogen atom located
at the 3-position of the imidazole ring provides a point for
hydrogen bonding of the receptor.37
Modifications to the original imidazole core led to the
development of olmesartan medoxomil by Sankyo chemists
(Fig. 4A).31,38 Olmesartan medoxomil exists as a prodrug
composed of the parent compound olmesartan that has been
esterified with a (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl
(medoxomil) group (Fig. 4A). Olmesartan medoxomil is
deesterified in vivo via the arylesterase enzyme. This enzyme
is found in both the intestine and plasma. The conversion of
olmesartan medoxomil to the active agent olmesartan occurs
rapidly via the breakdown of the medoxomil ester moiety.39
A wide variety of 4-position imidazole antagonists were
constructed, including alkyl, alkenyl, and hydroxyalkyl
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Mire et al J Cardiovasc Pharmacol ä  Volume 46, Number 5, November 2005
FIGURE 4. A, Chemical structures of olmesartan and olme-
sartan medoxomil. X-ray–determined structure of olmesartan.
B, Olmesartan has intramolecular hydrogen bonding between
the hydroxyl group and the carboxyl group.31,38
substituted derivatives. The resulting compounds were
evaluated for their A-II antagonistic activity using in vitro
binding affinity to AT1 receptors and intravenous and oral
inhibitory efficacy on the A-II pressor response in rats.31 When
the alkyl- and alkenyl-substituted molecules were examined
for biologic activity, it became evident that the presence of
bulky alkyl or alkenyl substituent groups at the imidazole 4-
position decreased the binding affinity of the molecule to the
AT1 receptor. In the case of unsubstituted hydrocarbons, an
increase in size of the substituent led to a reduction in binding
affinity such that H . CH3 ; CH2CH3 . C(=CH2)CH3 .
CH(CH3)2 in both 2#-tetrazole-biphenyl and 2#-carboxybi-
phenyl series (Fig. 5). Addition of the hydroxy group to the
alkyl groups (ie, formation of the hydroxyalkyl group)
remarkably enhanced the binding affinities of the antagonists.
In vivo antihypertensive activity of the hydroxyalkyl
substituted compounds (as compared with the unsubstituted
hydrocarbon analogues) was increased 100-fold versus
losartan.31 Additionally, it was found that hydroxyalkyl
substituents bulkier than C(CH3)2OH caused a reduction in
antagonist activity.
An assessment of the effect of the acidic substituent at
the biphenyl 2#-position was studied by examining the iden-
tical series of 4- and 5-imidazole derivatives.31 The use of 5-
substituted-1H-tetrazoles as bioisosteric replacements for car-
boxylic acids has been recently reviewed.40 For all derivatives,
the tetrazole-substituted molecules consistently had greater
antagonistic activity than the similarly substituted carboxylic
acid derivatives.
The end results from these studies show the importance
of a hydroxyl group at the 4-position of the imidazole ring for
high-affinity binding of olmesartan to the AT1 receptor. Also,
588
FIGURE 5. Analogues examined during olmesartan medoxomil
development.31
the presence of an intermediate-sized alkyl substituent in-
creased binding affinity, likely the result of a lipophilic inter-
action with the receptor, mimicking the isopropyl side chain
of the Ile5 amino acid in A-II. Thus, as a result of chemical
and biologic analyses, the C(CH3)2OH substituent at the im-
idazole 4-position was selected and found to provide for both
moderate bulk and hydrogen-bonding capability of olmesartan
medoxomil (Fig. 5).
In conjunction with the chemical and biologic studies
conducted, proton nuclear magnetic resonance spectra (1H
NMR) and x-ray structural analysis of olmesartan provided
additional insight into the key features of the molecule.31 The
x-ray structure revealed that an intramolecular hydrogen
bond formed between the hydroxyl group at the imidazole
4-position and the carboxylate anion at the imidazole 5-position
(Fig. 4B).31,38 Establishment of this hydrogen bond not only
appears to change the electrostatic nature of the imidazole
5-carboxy group but also may help direct the isopropyl
substituent (a gem-dimethyl group for olmesartan) at the
imidazole 4-position to a more favorable conformation within
the hydrophobic binding region of the AT1 receptor.31,41 This
idea was further supported through conformational analysis
techniques using the PM3 method of MOPAC (Molecular
Orbital Package). MOPAC is an all-purpose semiempirical
quantum mechanics program that is used as the basis for
quantitative SAR studies to predict structural and biologic
properties of molecules.42 This molecular modeling technique
generated a three-dimensional structure of olmesartan. A
stereochemical comparison with the C-terminal pentapeptide
of A-II suggested that olmesartan overlapped with this region
of A-II and emphasized the importance of the hydroxyl group
at the imidazole 4-position for optimal binding affinity and
antagonist properties.31
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J Cardiovasc Pharmacol ä  Volume 46, Number 5, November 2005
Mode of AT1 Receptor Antagonism
To date, many selective, potent, and orally available
ARBs have been developed and are used clinically to treat
hypertension and reduce end-organ damage associated with
diseases such as atherosclerosis and diabetes.16 Although all
ARBs bind with high affinity to the AT1 receptor,43 there are
differences in the modes of interaction of ARBs with the
receptor (Table 1).44 The binding of ARBs such as olmesartan,
valsartan, candesartan, telmisartan, and irbesartan to the AT1
receptor displays varying degrees of insurmountability. In con-
trast, losartan, eprosartan, and tasosartan display surmount-
able binding characteristics.43,45 A 2-state, 2-step antagonist
(A)–AT1 receptor (R) kinetic model has been proposed to best
explain the changes observed in the dose–response curves for
surmountable and insurmountable antagonists.46
In a study that compared olmesartan to losartan,
EXP3174, and candesartan, it was observed that olmesartan
behaved in an insurmountable manner, but the kinetics of the
inhibitory effect for olmesartan appeared to be greater than
that for the other ARBs,8 which may be related to structural
features unique to olmesartan.41 This apparent distinction may
result from the presence of the hydroxyisopropyl substituent at
the imidazole 4-position of olmesartan. This substituent can
hydrogen bond with the AT1 receptor and form an intra-
molecular hydrogen bond with the carboxylic acid moiety at
the imidazole 5-position of olmesartan (Fig. 6).41 Although
all ARBs share a common mechanism of action, differences
in molecular structure may lead to enhanced pharmacolog-
ical properties and help explain inherent differences in
efficacy.
THE PHARMACOLOGY OF
OLMESARTAN MEDOXOMIL
Olmesartan produces selective, insurmountable inhibi-
tion of the AT1 receptor and displays no AT2 receptor activity
(AT1 blockade is ;12,500-fold greater than that for AT2).8,47
Olmesartan medoxomil displays a rapid onset of action and a
long-lasting inhibition of A-II–induced pressor responses that
TABLE 1. A Summary of the Pharmacological Differences Between Surmountable and
Insurmountable Antagonism
Surmountable
Duration of physiological effect Short (minutes)
Receptor dissociation kinetics* Fast (k1 ; k21)
Effects on angiotensin II (A-II) Rightward shift
dose–response curve in curve (ED50)
Magnitude of the shift
is proportional to
antagonist concentration
No change
in maximal response
(efficacy) (Emax = E’max)
No change in Bmax
Receptor binding Antagonist can be reversed
by increasing A-II concentration
*All angiotensin receptor blockers (ARBs) dissociate from the AT1 receptor; no clinically used ARB binds irreversibly.
Bmax describes the number of A-II binding sites. Emax describes the maximal tissue response or efficacy for the agonist, A-II. Data derived from Vauquelin
et al.44
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Structure and Function of Olmesartan Medoxomil
may be the result of its pharmacokinetic properties and slow
dissociation from the AT1 receptor. As has been suggested
for candesartan cilexitil, the long antihypertensive actions of
olmesartan medoxomil may also result from drug accumula-
tion at the receptor level or drug reassociation to the receptor
after dissociation.45
An In Vitro Receptor Binding Profile of
Olmesartan on AT1 Receptors
The inhibitory effect of olmesartan on [125I]A-II binding
was compared with that of related ARBs from data obtained
using bovine adrenal cortex membranes that express AT1
receptors and bovine cerebellum membranes that express
AT2 receptors.8 Adrenal cortical membranes (10 mg) were in-
cubated with [125I]A-II (20 fmol) and increasing concen-
trations of olmesartan. The binding of [125I]A-II to cell
membranes was quantified using a radioreceptor assay.
The concentration of olmesartan required to produce 50%
inhibition of [125I]A-II binding (IC50) to the AT1 receptor in
adrenal cortex was 7.7 6 1.0 nM. An examination of studies
conducted using similar experimental conditions showed
that olmesartan binds the AT1 receptor with an affinity
comparable to those of valsartan and telmisartan but ;2.0-fold
greater than that of candesartan (Table 2). Olmesartan showed
no antagonist activity on AT2 receptors in cerebellar
membranes. Olmesartan’s affinity for the AT2 receptor in
these membranes was .100,000 nM or .12,500 times less
than that for the AT1 receptor.
Thus, although olmesartan and related ARBs are potent
inhibitors of binding of A-II to the AT1 receptor, these binding
studies showed comparable binding affinities between ARBs
that produce insurmountable AT1 blockade that is slightly
greater than that for agents that produce surmountable an-
tagonism. However, because these studies were not designed
to specifically examine the nature of receptor blockade or to
describe the differences in receptor kinetics, the results are
difficult to interpret mechanistically other than that these drugs
are potent, selective inhibitors of the AT1 receptor.
Insurmountable
Long (hours)
Slow, strong (k22 ... k2)
Modest shift
in curve (ED50 may increase)
Reduction in maximal
response (efficacy [Emax] decreases)
Bmax decreases
Antagonism cannot be completely reversed
by increasing agonist concentration
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Mire et al
FIGURE 6. Proposed interaction of olmesartan with the AT1
receptor.38
TISSUE-BINDING PROPERTIES: OLMESARTAN
AND RELATED ARBS
In addition to binding studies using cell membranes,
functional studies were conducted in A-II–challenged isolated
tissue preparations to obtain estimates of the efficacy and
potency of the drug. Olmesartan showed no inhibitory activity
on the contractile response of vascular tissue when depolariz-
ing agents such as potassium chloride or receptor-specific
agonists such as norepinephrine were used in rabbit aortic
preparations or histamine-induced contraction in guinea pig
tissue.8 However, olmesartan showed potent inhibition of
A-II–mediated vasoconstriction of isolated aortas. In these
studies, the tissue-blocking effects of the ARB are presented as
IC50 (molar concentration that is required for 50% inhibition
of the maximal response). The pharmacological activity of
olmesartan was assessed and showed a greater potency than
that of other ARBs when data were compared from similar
studies (Table 3).8,47–49 Specifically, olmesartan was 4.2-fold
more potent than valsartan, 30.7-fold more potent than
irbesartan, and 203-fold more potent than losartan.
TABLE 2. A Comparison of the Potency of Binding of Several
Arbs to Either AT1 or AT2 Receptors
IC50 (nM)
ARB AT1 (Adrenal Cortex)
Angiotensin II 1.5
Valsartan 6.5
Olmesartan* 7.7
Telmisartan 9.2
Candesartan 12
EXP3174* 16
Losartan potassium 92
*Indicates that these are the active forms of the molecule, not the prodrug.
Note that EXP3174 is the active metabolite of losartan. Telmisartan binding studies
were conducted using rat aortic smooth muscle cell preparations. See Koike et al47 for
additional details. Comparisons are based on data published from several studies (see text
for details) using similar study conditions.
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TABLE 3. A Comparison of the Potency of ARB Antagonism
Of A-II–Mediated Vasoconstriction in Isolated Aortic
Tissue Preparations
AT1 Functional Antagonism
ARB [IC50 (nM)]
Candesartan 0.11
Olmesartan 0.13
Eprosartan ;0.29
Telmisartan ;0.33
Valsartan ;0.55
EXP3174 2.45
Irbesartan 4.0
Losartan potassium 26.4
The olmesartan IC50 is derived from a pD2 of 9.9 (pD2 is the negative log of the IC50
value). The IC50 values for eprosartan, telmisartan, and valsartan were calculated from
their pKB values. Data derived from Mizuno et al,8 Merlos et al,48 Koike et al,47 and
Brunner.49 Note that comparisons of AT1 functional antagonism between ARBs are based
on data published from several different studies (see text for details) using isolated aortic
tissue preparations under similar study conditions.
Olmesartan antagonized the A-II–induced contraction
of isolated guinea pig aortas in a concentration-dependent
manner (Fig. 7).8 Olmesartan reduced the maximal response
(ie, contraction) induced by A-II. As an insurmountable an-
tagonist, olmesartan produced a distinctly nonparallel dis-
placement of the A-II concentration–response curve in these
tissues. In isolated tissue preparations, the antagonist effect of
olmesartan was increased as the time of drug exposure
increased, and activity remained for at least 90 minutes after
washout of the drug.8
ANTIHYPERTENSIVE EFFICACY: IN VIVO
ANIMAL MODELS
Inhibition of A-II–Mediated Pressor Response
Activation of AT1 receptors by exogenous (intravenous)
administration of A-II elicits a pressor response. The pressor
AT2 (Cerebellum)
0.57
.30,000
.100,000
— FIGURE 7. The effect of olmesartan on guinea pig aortic tissue
.100,000 contraction induced by A-II. Denuded guinea pig thoracic aortas
.100,000
were suspended in isolated organ baths containing Krebs-
Henseleit solution. Isometric tension was recorded, and A-II
.100,000
concentration–response curves were obtained in the absence and
presence of olmesartan (0.1 and 0.3 nM). The concentration of
olmesartan that produced half-maximal inhibition of the A-II
response (IC50) was 0.13 nM (Reprinted from European Journal of
Pharmacology, Vol. 285, Mizuno et al, Pharmacology of CS-866,
(1995), with permission from Elsevier).
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increases aldosterone levels and enhances sympathetic ner-

TABLE 4. The Inhibitory Effects of ARBs to A-II Pressor
vous system activity.57
Responses In Vivo
In Goldblatt (2K1C) renal hypertensive rats, single oral
Inhibition of A-II Pressor
Responses
doses of olmesartan medoxomil (0.01–0.3 mg/kg) produce a
dose-dependent reduction in blood pressure (Fig. 8).8,41,47
ED50 Relative Olmesartan
ARB (mg/kg) Potency
Inferential data examination from comparable studies for can-
desartan cilexitil, irbesartan, and valsartan are also shown us-
Olmesartan 0.0079 —
ing the same model. The data for the efficacy of each drug in
Candesartan (active metabolite) 0.03 3.8
this model were expressed as the percentage change from con-
Eprosartan 0.10 13
trol value in each study conducted, and data from each study
Telmisartan 0.10 13
were best fit using the Hill equation.41 When these studies were
EXP-3174
(losartan active metabolite) 0.27* 34
compared, the maximal dose of olmesartan medoxomil ad-
Irbesartan 0.45 57
ministered (0.3 mg/kg) produced a 60 mm Hg reduction in
Losartan potassium 0.70 89
blood pressure 3 hours after administration. This response was
Valsartan 10† N/A
similar to that for the 10-mg/kg dose of candesartan and the
30-mg/kg dose of valsartan.
*An anesthetized pithed rat model was used. Other studies used conscious or From the use of these in vitro and in vivo animal models,
anesthetized animals.
†Only an oral ED10 value could be determined in pithed, anesthetized rats. an understanding of the general pathophysiological principles
Data derived from Cazaubon et al,50 Criscione et al,51 Nishikawa et al,52 Mizuno associated with hypertension has been developed. In turn,
et al,8 and Yanagisawa et al.31 these models have lent themselves to characterizing the
Note that comparisons of inhibition of A-II pressor responses between ARBs are
based on data published from several different studies (see text for details). pharmacological potency and efficacy of ARBs that are used
clinically.

response model has routinely been used to assess the efficacy POTENTIAL CLINICAL SIGNIFICANCE
and potency of most ARBs currently used in the clinic. A ARBs share similar structural elements that are required
summary of the results from similar studies but conducted by for effective antagonism of the AT1 receptor. However,
different authors is presented in Table 4.8,31,50–52 A comparison olmesartan medoxomil has unique stereoelectronic features
of pressor response data shows that olmesartan medoxomil that distinguish it from other members of the class. An addi-
is ;4 times more potent than is candesartan and ;89 times tional binding site has been added through incorporation of
more potent than is losartan in this animal model. a hydroxyisopropyl substituent at the imidazole 4-position of
Although all of the ARBs examined in these different olmesartan medoxomil. The hydrogen bonding and hydro-
studies inhibited A-II–mediated pressor responses, drug effects phobic interaction capability provided by this hydroxyl group
were variable and time-dependent. Of all the ARBs examined, and isopropyl group, respectively, increases the binding affi-
olmesartan medoxomil produced the greatest dose-dependent nity of olmesartan medoxomil with the AT1 receptor and
inhibition of the pressor response (Table 4). Olmesartan may help explain its enhanced clinical efficacy. This clinical
medoxomil (0.01 mg/kg) produced ;85% inhibition of the
pressor response within 1 hour after dosing, whereas EXP3174
produced ;70% reduction at a dose of 1 mg/kg (100 times the
olmesartan medoxomil dose), and irbesartan produced ;60%
inhibition at a dose of 10 mg/kg (1000 times the olmesartan
medoxomil dose). This pressor response model has useful
links to human studies where a similar A-II challenge is used
to evaluate the relationship between effectiveness and dose of
a drug.53

GOLDBLATT RENAL HYPERTENSIVE RATS

Hypertension develops in animals in which unilateral
kidney stenosing is produced by placement of a vascular clip
on the renal artery. Goldblatt and colleagues54 published
the first results of a classic study in which experimental
constriction of a renal artery resulted in sustained systemic
hypertension—the 2-kidney, 1-clip (2K1C) model. In 2K1C
models used to evaluate ARBs, constriction of the renal artery FIGURE 8. The antihypertensive effect of olmesartan and
reduces perfusion pressure, resulting in an increase in renin related ARBs in Goldblatt (2K1C) renal hypertensive rats
synthesis and release from the clipped kidney.55,56 The 3 hours postdose.8,41,47 Note that comparisons are based on
elevated circulating A-II level is a crucial factor in the data published from several studies (see text for details) using
pathogenesis of hypertension in this model because A-II the same animal model and similar study conditions.

q 2005 Lippincott Williams & Wilkins 591

Mire et al J Cardiovasc Pharmacol ä  Volume 46, Number 5, November 2005
efficacy has been demonstrated in a 12-week, randomized,
parallel-group study with recommended starting doses of
olmesartan medoxomil (20 mg/d), losartan potassium (50 mg/d),
valsartan (80 mg/d), and irbesartan (150 mg/d). Olmesartan
medoxomil 20 mg/d was significantly more effective than
starting doses of losartan potassium, valsartan, and irbesartan
in reducing cuff DBP in patients with essential hypertension.58
This was further demonstrated with significant differences in
24-hour ambulatory blood pressure goal rates versus losartan
potassium and valsartan and numerically greater differences
from that of irbesartan.59 The clinical results are consistent
with the marked, long-lasting antihypertensive efficacy of
olmesartan medoxomil observed in vivo, which may result
from a unique pharmacological interaction of the molecule
with the AT1 receptor. The nature of this interaction at the
receptor level is being further investigated.
Although the receptor binding interactions resulting
from the unique structural features of olmesartan medoxomil
are yet to be fully characterized, the observations made at the
receptor, tissue, animal, and clinical levels are consistent. This
information provides a framework for comparing angiotensin
receptor antagonists and may help explain the clinical dif-
ferences seen within the class.
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