Discovery and development of angiotensin receptor blockers
Encyclopedia
The angiotensin receptor blockers (ARBs), also called angiotensin (AT1) receptor antagonists or sartans, are a group of anti-hypertensive drugs that act by blocking the effects of the hormone
angiotensin II (Ang II) in the body, thereby lowering blood pressure
. Their structure is similar to Ang II and they bind to Ang II receptors
as inhibitors.E.g.,[T24 from Rhys Healthcare]
ARBs are widely used drugs in the clinical setting today, their main indications
being mild to moderate hypertension
, chronic heart failure, secondary stroke
prevention and diabetic nephropathy
.
The discovery and development of ARBs is a demonstrative example of modern rational drug design and how that design can be used to gain further knowledge of physiological systems, in this case, the characterization of the subtypes of Ang II receptors.
, which they named renin
, that caused a rise in blood pressure. In the 1930s, Goldblatt conducted experiments where he constricted the renal blood flow in dogs and he found that the ischaemic kidneys did in fact secrete a chemical that caused vasoconstriction
. In 1939 it was discovered that renin itself did not cause the rise in blood pressure but was an enzyme
which catalyzed the formation of the substances that were responsible, namely, angiotensin I (Ang I) and Ang II.
In the 1970s scientists first observed that Ang II harms the heart and kidneys and it was also witnessed that individuals with high levels of renin activity in plasma
were at increased risk of myocardial infarction
and stroke.
With the introduction of angiotensin converting enzyme (ACE) inhibitors in the late 1970s it was confirmed that Ang II plays an important role in regulating blood pressure and electrolyte
and fluid balance.
Before that attempts had been made to develop useful Ang II receptor antagonists and initially, the main focus was on angiotensin peptide
analogues. Saralasin
and other Ang II analogues were potent Ang II receptor blockers but the main problem was a lack of oral bioavailability
.
In the early 1980s it was noted that a series of imidazole-5-acetic acid
derivatives
diminished blood pressure responses to Ang II in rats. Two compounds, S-8307 and S-8308, were later found to be highly specific and promising non-peptide Ang II receptor antagonists but using molecular modeling it was seen that their structures would have to mimic
more closely the pharmacophore
of Ang II. Structural modifications were made and the orally active, potent and selective nonpeptide AT1 receptor blocker losartan
was developed. In 1995 losartan was approved for clinical use in the United States and since then six additional ARBs have been approved. These drugs are known for their excellent side-effects
profiles, which clinical trials have shown to be similar to that of placebos.
and AT2
. These receptors are members of the G protein-coupled receptors family which are seven transmembrane helices, connected by interchanging extracellular
and intracellular
loops.
Each G protein-coupled receptor
couples to a specific G-protein which leads to activation of a special effector system. AT1 receptors are for instance primarily coupled through the Gq/11 group of G-proteins.
Two more angiotensin receptors have been described, AT3 and AT4, but their role is still unknown.
AT2 receptors are highly expressed in the developing fetus
but they decline rapidly after birth. In the adult, AT2 receptors are present only at low levels and are mostly found in the heart, adrenal glands, uterus, ovaries, kidneys and brain.
, aldosterone
release, renal sodium reabsorption and vasopressin
secretion. The AT2 receptor also takes part in regulation of blood pressure and renal function but mediates antagonistic
effects compared to the AT1 receptor.
Ang II binds to AT1 receptors via various binding sites. The primary binding site is at the extracellular region of the AT1 receptor where Ang II interacts with residues in the N-terminus of the AT1 receptor and its first and third extracellular loops. The transmembrane helices also contribute to the binding via the C-terminal carboxyl group that interacts with Lys
199 in the upper part of helix 5 of the receptor, see figure 1 for details.
The ionic bridge formed between Lys
199 and the carboxyl terminal group of the Phe
8 residue of Ang II is most likely stabilized by the Trp
253 residue. In addition, Phe
259 and Asp
263 in transmembrane helix 6 and Lys
102 and Ser
105 in the outer region of transmembrane helix 3, have also been implicated in Ang II binding. This region may possibly participate in the stabilization of the receptor‘s ratification and in the formation of the intramembrane binding pocket.
Blood pressure and fluid and electrolyte homeostasis
is regulated by the renin-angiotensin-aldosterone-system
.
Renin
, an enzyme released from the kidneys, converts the inactive plasma protein angiotensinogen into angiotensin I (Ang I). Then Ang I is converted to Ang II with angiotensin converting enzyme (ACE), see figure 2. Ang II in plasma then binds to AT-receptors.
ARBs are blocking the last part of the renin-angiotensin pathway
and block the pathway more specifically than ACE inhibitors.
The AT1 receptor mediates Ang II to cause increased cardiac contractility, sodium reabsorption and vasoconstriction which all lead to increased blood pressure. By blocking AT1 receptors, ARBs lead to lower blood pressure.
An insurmountable inhibition of the AT1 receptor is achieved when the maximum response of Ang II cannot be restored in the presence of the ARB, no matter how high the concentration
of Ang II is.
The angiotensin receptor blockers can inhibit the receptor in a competitive surmountable, competitive insurmountable or noncompetitive fashion, depending upon the rate at which they dissociate from the receptor.
Because of saralasin
, the first Ang II antagonist, and the development of the first ACE inhibitor
captopril
, it was generally acknowledged that Ang II receptor antagonists might be promising as effective antihypertensive
agents.
Saralasin was developed in the early 1970s and is an octapeptide analogue of Ang II, where the amino acids Asp
1, Ile
5 and Phe
8 have been replaced with Ser
1, Val
5 and Ala
8, respectively. Saralasin was not orally bioavailable, had short duration of action and showed partial agonist
activity and therefore it was not suitable as a drug.
Thus the goal was to develop a smaller nonpeptide substance with similar inhibition and binding features. At this time, a group at DuPont
had already started the screening of nonpeptide mimics of Ang II using existing substances from chemical libraries.
Research investigators at Takeda
discovered in 1982 the weak nonpeptide Ang II antagonists S-8307 and S-8308 from a group of 1-benzylimidazole
-5-acetic acid derivatives. S-8307 and S-8308 have moderate potency
, short duration of action and limited oral bioavailability, however they are selective and competitive AT1 receptor antagonists without partial agonist activity. A group at DuPont postulated that both Ang II and the Takeda leads were bound at the same receptor site. These two substances served as lead compounds for further optimization of AT1 receptor blockers.
Using nuclear magnetic resonance
studies on the spatial structure of Ang II, scientist at DuPont discovered that the Takeda structures had to be enlarged at a particular position to resemble more closely the much larger peptide Ang II.
Computer modeling was used to compare S-8308 and S-8307 with Ang II and it was seen that Ang II contains two acidic residues near the NH2 terminus. These groups were not mimicked by the Takeda leads and therefore it was hypothesized that acidic functional groups would have to be added to the compounds.
The 4-carboxy-derivative EXP-6155 had a binding activity which was ten-fold greater than that of S-8308 which further strengthened this hypothesis
.
By replacing the 4-carboxy-group with a 2-carboxy-benzamido-moiety the compound EXP-6803 was synthesized. It had highly increased binding affinity but was only active when administered intravenously.
Replacing the 2-carboxy-benzamido-group with a 2-carboxy-phenyl-group created the lipophilic
biphenyl
-containing EXP-7711, which exhibited good oral activity but slightly less affinity for the AT1 receptor.
Then the polar
carboxyl group was replaced with a more lipophilic tetrazole
group in order to increase oral bioavailability and duration of action further and the compound thus formed was named losartan. This development took place in 1986 and losartan became the first successful Ang II antagonist
drug, approved as such in the United States in 1995 and was marketed by Merck
.
This development was laborious and expensive work and it is approximated that the process from the Takeda structures to the final substance, losartan, took more than fifty person-years in biological testing and chemical modifications.
Using a different lead optimization from S-8308, eprosartan
was developed by SmithKline Beecham in 1992. Eprosartan does not have a biphenyl-methyl structure but in order to mimic the C-terminal end of Ang II the 5-acetic acid group was replaced with an a-thienylacrylic acid and a 4-carboxy-moiety. Eprosartan is a selective, potent and competitive AT1 antagonist and its binding to AT1 receptors is rapid, reversible, saturable and of high affinity.
, candesartan
, irbesartan
, telmisartan
and olmesartan
all contain a biphenyl-methyl group.
Losartan is partly metabolized to its 5-carboxylic acid
metabolite
EXP 3174, which is a more potent AT1 receptor antagonist than its parent compound and has been a model for the continuing development of several other ARBs.
Valsartan, candesartan and irbesartan were all developed in 1990.
Valsartan, first marketet by Novartis
, is a nonheterocyclic ARB, where the imidazole of losartan has been replaced by an acyl
ated amino acid
.
Irbesartan was developed by Sanofi Research and is longer acting than valsartan and losartan and it has an imidazolinone ring where a carbonyl
group functions as a hydrogen bond
acceptor instead of the hydroxymethyl
group in losartan. Irbesartan is a non-competitive inhibitor.
Candesartan cilexetil (TCV 116) is a benzimidazole which was developed at Takeda and is an ester
carbonate
prodrug
. In vivo
, it is rapidly converted to the much more potent corresponding 7-carboxylic acid, candesartan. In the interaction of candesartan with AT1 receptor the carboxyl group of the benzimidazole ring plays an important role. Candesartan and its prodrug have stronger blood pressure lowering effects than EXP 3174 and losartan.
Telmisartan, which was discovered and developed in 1991 by Boehringer Ingelheim, has carboxylic acid as the biphenyl acidic group. It has the longest elimination half-life
of the ARBs or about 24 hours.
Olmesartan medoxomil was developed by Sankyo
in 1995 and is the newest ARB on the market, marketed in 2002. It is an ester prodrug like candesartan cilexetil. In vivo, the prodrug is completely and rapidly hydrolyzed to the active acid form, olmesartan (RNH-6270). It has a hydroxyisopropyl
group connected to the imidazole ring in addition to the carboxyl group.
There are three functional groups that are the most important parts for the bioactivity of ARBs, see figure 1 for details.
The first one is the imidazole ring that binds to amino acids in helix 7 (Asn
295). The second group is the biphenyl-methyl group that binds to amino acids in both helices 6 and 7 (Phe
301, Phe
300, Trp
253 and His
256). The third one is the tetrazole
group that interacts with amino acids in helices 4 and 5 (Arg
167 and Lys
199).
The tetrazole group has been successfully replaced by a carboxylic acid group as is the case with telmisartan.
Structure-activity relationship (SAR)
Most of the ARBs have the same pharmacophore
so the difference in their biochemical and physiological effects is mostly due to different substituent
s. Activity of a drug is dependent of its affinity for the substrate site and the length of time it binds to the site.
Lipophilic substituents like the linear alkyl group at the 2-position on the imidazole ring together with the biphenyl-methyl group, associate with hydrophobic pockets of the receptor. An acidic group like tetrazole, CO2H or NHSO2CF3 at the 1-position of the biphenyl-methyl group will bind to a basic position in the receptor and are required for potent antagonistic
activity.
In valsartan, the imidazole ring of losartan has been replaced with an acylated amino acid.
Several substituents have been tried at the 4- and 5- positions on the imidazole ring. The chloro and hydroxymethyl groups connected to these positions in losartan are probably not of much importance in receptor binding since the other ARBs do not possess these functional groups and have comparable or better binding affinities than losartan. Irbesartan has a carbonyl group at the 5-position, functioning as a hydrogen bond acceptor in place of the hydroxymethyl group of losartan, resulting in a longer binding to the receptor.
The structure of eprosartan is the one that differs most from the other ARBs, the usual biphenyl-methyl group has been replaced by a carboxy benzyl
group that mimics more closely the phenol
ic moiety of Tyr
4 group of Ang II. This change results in a stronger binding to the receptor but the biochemical and physiological effects are not significantly improved.
Telmisartan has a carboxylic acid at the 2-position of the biphenyl-methyl group and is more potent than the tetrazole analogue.
It has been reported that imidazoles that have hydroxymethyl and carboxy groups at the 4- and 5 position, possessed potent antagonistic activity, caused by the hydrogen bonding and hydrophilicity of the hydroxymethyl group.
It has also been reported that an hydroxy group in the 4-position on the imidazole ring, plays an important role in the binding affinity and compensates for the disadvantage of lipophilicity of the bulky alkyl group.
These results show that a medium-sized hydroxy alkyl group, such as CHMeOH and CMe2OH, is favorable for the substituent of the 4-position on the imidazole ring. Furthermore, the ion
izable group is favorable for the binding affinity.
Candesartan and olmesartan have the highest affinity for the AT1 receptors, followed by irbesartan and eprosartan. Valsartan, telmisartan and EXP 3174 have similar affinities that are about ten-fold less than that of candesartan. Losartan has the least affinity. ARBs' affinity for the AT2 receptor is generally much lower (or around 10,000 times less) then for the AT1 subtype. Therefore they allow unhindered stimulation of the AT2 receptor.
ARBs have a large therapeutic index
and therefore their (mostly low) oral bioavailability does not appear to be of clinical significance.
As can be seen in table 1, these drugs are highly plasma protein-bound and therefore oral administration once a day should provide sufficient antihypertensive
effects.
Around 14 % of orally ingested losartan is metabolized to its 5-carboxylic acid metabolite
EXP 3174. As mentioned before, candesartan cilexetil and olmesartan medoxomil are inactive ester prodrugs that are completely hydrolyzed to their active forms by esterases during absorption
from the gastrointestinal tract
. These three metabolites are more potent AT1 receptor antagonists than their prodrugs. The other ARBs do not have active metabolites.
All of the ARBs, except for telmisartan and olmesartan, are metabolized in some way by the cytochrome P450 (CYP) enzyme 2C9
, that is found in the human liver. CYP2C9
is for example responsible for the metabolizing of losartan to EXP 3174 and the slow metabolizing of valsartan and candesartan to their inactive metabolites. Telmisartan is, on the other hand, in part metabolized by glucuronidation
and olmesartan is excreted as the unchanged drug.
Telmisartan is the only ARB that can cross the blood-brain barrier
and can therefore inhibit centrally mediated effects of Ang II, contributing to even better blood pressure control.
All of the ARBs have the same mechanism of action
and differences in their potency can be related to their different pharmacokinetic profiles. A few clinical head-to-head comparisons have been made and candesartan, irbesartan and telmisartan appear to be slightly more effective than losartan in lowering blood pressure. This difference may be related to different strengths of activity at the receptor level, such as duration and strength of receptor binding.
Several new nonpeptide ARBs are undergoing clinical trials or are at pre-clinical stages of development. Among these are embusartan (BAY 10-6734 or BAY 10-6734), KRH-594, fonsartan (HR 720) and pratosartan (KT3-671). Pratosartan, for example, has a novel structure: a seven-membered ring that bears an oxo
moiety (C=O) fused to the imidazole ring (figure 4), and its affinity for the AT1 receptor is about 7 times higher than losartan's. The purpose of the oxo
group is similar to that of the carboxylic acid groups on other ARBs.
Other attributes of ARBs are also under investigation, such as the positive effects of telmisartan on lipid
and glucose metabolism and losartan's effects of lowering uric acid
levels. Such effects might lead to new indications for these drugs but further research is needed.
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
angiotensin II (Ang II) in the body, thereby lowering blood pressure
Blood pressure
Blood pressure is the pressure exerted by circulating blood upon the walls of blood vessels, and is one of the principal vital signs. When used without further specification, "blood pressure" usually refers to the arterial pressure of the systemic circulation. During each heartbeat, BP varies...
. Their structure is similar to Ang II and they bind to Ang II receptors
Angiotensin receptor
The angiotensin receptors are a class of G protein-coupled receptors with angiotensin II as their ligands. They are important in the renin-angiotensin system: they are responsible for the signal transduction of the vasoconstricting stimulus of the main effector hormone, angiotensin...
as inhibitors.E.g.,[T24 from Rhys Healthcare]
ARBs are widely used drugs in the clinical setting today, their main indications
Indication (medicine)
In medicine, an indication is a valid reason to use a certain test, medication, procedure, or surgery. The opposite of indication is contraindication.-Drugs:...
being mild to moderate hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
, chronic heart failure, secondary stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
prevention and diabetic nephropathy
Diabetic nephropathy
Diabetic nephropathy , also known as Kimmelstiel-Wilson syndrome, or nodular diabetic glomerulosclerosis and intercapillary glomerulonephritis, is a progressive kidney disease caused by angiopathy of capillaries in the kidney glomeruli. It is characterized by nephrotic syndrome and diffuse...
.
The discovery and development of ARBs is a demonstrative example of modern rational drug design and how that design can be used to gain further knowledge of physiological systems, in this case, the characterization of the subtypes of Ang II receptors.
History
In 1898 physiologists Tigerstedt and Bergmann experimented with rabbits by injecting them with kidney extracts. Their results suggested that the kidneys produced a proteinProtein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
, which they named renin
Renin
Renin , also known as an angiotensinogenase, is an enzyme that participates in the body's renin-angiotensin system -- also known as the Renin-Angiotensin-Aldosterone Axis -- that mediates extracellular volume , and arterial vasoconstriction...
, that caused a rise in blood pressure. In the 1930s, Goldblatt conducted experiments where he constricted the renal blood flow in dogs and he found that the ischaemic kidneys did in fact secrete a chemical that caused vasoconstriction
Vasoconstriction
Vasoconstriction is the narrowing of the blood vessels resulting from contraction of the muscular wall of the vessels, particularly the large arteries, small arterioles and veins. The process is the opposite of vasodilation, the widening of blood vessels. The process is particularly important in...
. In 1939 it was discovered that renin itself did not cause the rise in blood pressure but was an enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
which catalyzed the formation of the substances that were responsible, namely, angiotensin I (Ang I) and Ang II.
In the 1970s scientists first observed that Ang II harms the heart and kidneys and it was also witnessed that individuals with high levels of renin activity in plasma
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
were at increased risk of myocardial infarction
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
and stroke.
With the introduction of angiotensin converting enzyme (ACE) inhibitors in the late 1970s it was confirmed that Ang II plays an important role in regulating blood pressure and electrolyte
Electrolyte
In chemistry, an electrolyte is any substance containing free ions that make the substance electrically conductive. The most typical electrolyte is an ionic solution, but molten electrolytes and solid electrolytes are also possible....
and fluid balance.
Before that attempts had been made to develop useful Ang II receptor antagonists and initially, the main focus was on angiotensin peptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
analogues. Saralasin
Saralasin
Saralasin is a competitive inhibitor of angiotensin II. It is an angiotensin II analogue, containing sarcosine-1 and alanine-8, hence the name ....
and other Ang II analogues were potent Ang II receptor blockers but the main problem was a lack of oral bioavailability
Bioavailability
In pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...
.
In the early 1980s it was noted that a series of imidazole-5-acetic acid
Acetic acid
Acetic acid is an organic compound with the chemical formula CH3CO2H . It is a colourless liquid that when undiluted is also called glacial acetic acid. Acetic acid is the main component of vinegar , and has a distinctive sour taste and pungent smell...
derivatives
Derivative (chemistry)
In chemistry, a derivative is a compound that is derived from a similar compound by some chemical or physical process. In the past it was also used to mean a compound that can be imagined to arise from another compound, if one atom is replaced with another atom or group of atoms, but modern...
diminished blood pressure responses to Ang II in rats. Two compounds, S-8307 and S-8308, were later found to be highly specific and promising non-peptide Ang II receptor antagonists but using molecular modeling it was seen that their structures would have to mimic
Mimic
In evolutionary biology, mimicry is the similarity of one species to another which protects one or both. This similarity can be in appearance, behaviour, sound, scent and even location, with the mimics found in similar places to their models....
more closely the pharmacophore
Pharmacophore
thumb|right|300px|An example of a pharmacophore model.A pharmacophore is an abstract description of molecular features which are necessary for molecular recognition of a ligand by a biological macromolecule....
of Ang II. Structural modifications were made and the orally active, potent and selective nonpeptide AT1 receptor blocker losartan
Losartan
Losartan is an angiotensin II receptor antagonist drug used mainly to treat high blood pressure . Losartan was the first angiotensin II receptor antagonist to be marketed. Losartan potassium is marketed by Merck & Co. Inc. under the trade name Cozaar...
was developed. In 1995 losartan was approved for clinical use in the United States and since then six additional ARBs have been approved. These drugs are known for their excellent side-effects
Adverse effect (medicine)
In medicine, an adverse effect is a harmful and undesired effect resulting from a medication or other intervention such as surgery.An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. If it results from an unsuitable or incorrect dosage or...
profiles, which clinical trials have shown to be similar to that of placebos.
The angiotensin II receptor
The actions of Ang II are mediated by angiotensin receptors, AT1Angiotensin II receptor type 1
Angiotensin II receptor, type 1 or AT1 receptor is an angiotensin receptor. It has vasopressor effects and regulates aldosterone secretion. It is an important effector controlling blood pressure and volume in the cardiovascular system...
and AT2
Angiotensin II receptor type 2
Angiotensin II receptor type 2, also known as the AT2 receptor is a protein that in humans is encoded by the AGTR2 gene.- Function :...
. These receptors are members of the G protein-coupled receptors family which are seven transmembrane helices, connected by interchanging extracellular
Extracellular
In cell biology, molecular biology and related fields, the word extracellular means "outside the cell". This space is usually taken to be outside the plasma membranes, and occupied by fluid...
and intracellular
Intracellular
Not to be confused with intercellular, meaning "between cells".In cell biology, molecular biology and related fields, the word intracellular means "inside the cell".It is used in contrast to extracellular...
loops.
Each G protein-coupled receptor
G protein-coupled receptor
G protein-coupled receptors , also known as seven-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptor, and G protein-linked receptors , comprise a large protein family of transmembrane receptors that sense molecules outside the cell and activate inside signal...
couples to a specific G-protein which leads to activation of a special effector system. AT1 receptors are for instance primarily coupled through the Gq/11 group of G-proteins.
Two more angiotensin receptors have been described, AT3 and AT4, but their role is still unknown.
Distribution in the body
AT1 receptors are mainly found in the heart, adrenal glands, brain, liver and kidneys. Their main role is to regulate blood pressure as well as fluid and electrolyte balance.AT2 receptors are highly expressed in the developing fetus
Fetus
A fetus is a developing mammal or other viviparous vertebrate after the embryonic stage and before birth.In humans, the fetal stage of prenatal development starts at the beginning of the 11th week in gestational age, which is the 9th week after fertilization.-Etymology and spelling variations:The...
but they decline rapidly after birth. In the adult, AT2 receptors are present only at low levels and are mostly found in the heart, adrenal glands, uterus, ovaries, kidneys and brain.
Functions
Most of the known actions of Ang II are mediated through the AT1 receptors, for example vasoconstrictionVasoconstriction
Vasoconstriction is the narrowing of the blood vessels resulting from contraction of the muscular wall of the vessels, particularly the large arteries, small arterioles and veins. The process is the opposite of vasodilation, the widening of blood vessels. The process is particularly important in...
, aldosterone
Aldosterone
Aldosterone is a hormone that increases the reabsorption of sodium ions and water and the release of potassium in the collecting ducts and distal convoluted tubule of the kidneys' functional unit, the nephron. This increases blood volume and, therefore, increases blood pressure. Drugs that...
release, renal sodium reabsorption and vasopressin
Vasopressin
Arginine vasopressin , also known as vasopressin, argipressin or antidiuretic hormone , is a neurohypophysial hormone found in most mammals, including humans. Vasopressin is a peptide hormone that controls the reabsorption of molecules in the tubules of the kidneys by affecting the tissue's...
secretion. The AT2 receptor also takes part in regulation of blood pressure and renal function but mediates antagonistic
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
effects compared to the AT1 receptor.
Binding pockets
Lysine
Lysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....
199 in the upper part of helix 5 of the receptor, see figure 1 for details.
The ionic bridge formed between Lys
Lysine
Lysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....
199 and the carboxyl terminal group of the Phe
PHE
PHE may refer to:* Population Health and Environment , an approach to development that integrates health or family planning with conservation efforts* Paramount Home Entertainment* BitTorrent protocol encryption...
8 residue of Ang II is most likely stabilized by the Trp
Tryptophan
Tryptophan is one of the 20 standard amino acids, as well as an essential amino acid in the human diet. It is encoded in the standard genetic code as the codon UGG...
253 residue. In addition, Phe
PHE
PHE may refer to:* Population Health and Environment , an approach to development that integrates health or family planning with conservation efforts* Paramount Home Entertainment* BitTorrent protocol encryption...
259 and Asp
Aspartic acid
Aspartic acid is an α-amino acid with the chemical formula HOOCCHCH2COOH. The carboxylate anion, salt, or ester of aspartic acid is known as aspartate. The L-isomer of aspartate is one of the 20 proteinogenic amino acids, i.e., the building blocks of proteins...
263 in transmembrane helix 6 and Lys
Lysine
Lysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....
102 and Ser
Serine
Serine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:...
105 in the outer region of transmembrane helix 3, have also been implicated in Ang II binding. This region may possibly participate in the stabilization of the receptor‘s ratification and in the formation of the intramembrane binding pocket.
Mechanism of action
Homeostasis
Homeostasis is the property of a system that regulates its internal environment and tends to maintain a stable, constant condition of properties like temperature or pH...
is regulated by the renin-angiotensin-aldosterone-system
Renin-angiotensin system
The renin-angiotensin system or the renin-angiotensin-aldosterone system is a hormone system that regulates blood pressure and water balance....
.
Renin
Renin
Renin , also known as an angiotensinogenase, is an enzyme that participates in the body's renin-angiotensin system -- also known as the Renin-Angiotensin-Aldosterone Axis -- that mediates extracellular volume , and arterial vasoconstriction...
, an enzyme released from the kidneys, converts the inactive plasma protein angiotensinogen into angiotensin I (Ang I). Then Ang I is converted to Ang II with angiotensin converting enzyme (ACE), see figure 2. Ang II in plasma then binds to AT-receptors.
ARBs are blocking the last part of the renin-angiotensin pathway
Renin-angiotensin system
The renin-angiotensin system or the renin-angiotensin-aldosterone system is a hormone system that regulates blood pressure and water balance....
and block the pathway more specifically than ACE inhibitors.
The AT1 receptor mediates Ang II to cause increased cardiac contractility, sodium reabsorption and vasoconstriction which all lead to increased blood pressure. By blocking AT1 receptors, ARBs lead to lower blood pressure.
An insurmountable inhibition of the AT1 receptor is achieved when the maximum response of Ang II cannot be restored in the presence of the ARB, no matter how high the concentration
Concentration
In chemistry, concentration is defined as the abundance of a constituent divided by the total volume of a mixture. Four types can be distinguished: mass concentration, molar concentration, number concentration, and volume concentration...
of Ang II is.
The angiotensin receptor blockers can inhibit the receptor in a competitive surmountable, competitive insurmountable or noncompetitive fashion, depending upon the rate at which they dissociate from the receptor.
Drug discovery and development
Development from saralasin to losartan and eprosartan
For a simple overview of the development of ARBs, see figure 3.Because of saralasin
Saralasin
Saralasin is a competitive inhibitor of angiotensin II. It is an angiotensin II analogue, containing sarcosine-1 and alanine-8, hence the name ....
, the first Ang II antagonist, and the development of the first ACE inhibitor
ACE inhibitor
ACE inhibitors or angiotensin-converting enzyme inhibitors are a group of drugs used primarily for the treatment of hypertension and congestive heart failure...
captopril
Captopril
Captopril is an angiotensin-converting enzyme inhibitor used for the treatment of hypertension and some types of congestive heart failure. Captopril was the first ACE inhibitor developed and was considered a breakthrough both because of its novel mechanism of action and also because of the...
, it was generally acknowledged that Ang II receptor antagonists might be promising as effective antihypertensive
Antihypertensive
The antihypertensives are a class of drugs that are used to treat hypertension . Evidence suggests that reduction of the blood pressure by 5 mmHg can decrease the risk of stroke by 34%, of ischaemic heart disease by 21%, and reduce the likelihood of dementia, heart failure, and mortality from...
agents.
Saralasin was developed in the early 1970s and is an octapeptide analogue of Ang II, where the amino acids Asp
Aspartic acid
Aspartic acid is an α-amino acid with the chemical formula HOOCCHCH2COOH. The carboxylate anion, salt, or ester of aspartic acid is known as aspartate. The L-isomer of aspartate is one of the 20 proteinogenic amino acids, i.e., the building blocks of proteins...
1, Ile
Isoleucine
Isoleucine is an α-amino acid with the chemical formula HO2CCHCHCH2CH3. It is an essential amino acid, which means that humans cannot synthesize it, so it must be ingested. Its codons are AUU, AUC and AUA....
5 and Phe
PHE
PHE may refer to:* Population Health and Environment , an approach to development that integrates health or family planning with conservation efforts* Paramount Home Entertainment* BitTorrent protocol encryption...
8 have been replaced with Ser
Serine
Serine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:...
1, Val
Valine
Valine is an α-amino acid with the chemical formula HO2CCHCH2. L-Valine is one of 20 proteinogenic amino acids. Its codons are GUU, GUC, GUA, and GUG. This essential amino acid is classified as nonpolar...
5 and Ala
Alanine
Alanine is an α-amino acid with the chemical formula CH3CHCOOH. The L-isomer is one of the 20 amino acids encoded by the genetic code. Its codons are GCU, GCC, GCA, and GCG. It is classified as a nonpolar amino acid...
8, respectively. Saralasin was not orally bioavailable, had short duration of action and showed partial agonist
Partial agonist
Partial agonists bind and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist...
activity and therefore it was not suitable as a drug.
Thus the goal was to develop a smaller nonpeptide substance with similar inhibition and binding features. At this time, a group at DuPont
DuPont
E. I. du Pont de Nemours and Company , commonly referred to as DuPont, is an American chemical company that was founded in July 1802 as a gunpowder mill by Eleuthère Irénée du Pont. DuPont was the world's third largest chemical company based on market capitalization and ninth based on revenue in 2009...
had already started the screening of nonpeptide mimics of Ang II using existing substances from chemical libraries.
Research investigators at Takeda
Takeda Pharmaceutical Company
is the largest pharmaceutical company in Japan and Asia and a top 15 pharmaceutical company. The company has over 19,000 employees worldwide and achieved $15.7 billion USD in revenue during the 2008 fiscal year...
discovered in 1982 the weak nonpeptide Ang II antagonists S-8307 and S-8308 from a group of 1-benzylimidazole
Benzimidazole
Benzimidazole is a heterocyclic aromatic organic compound. This bicyclic compound consists of the fusion of benzene and imidazole. The most prominent benzimidazole compound in nature is N-ribosyl-dimethylbenzimidazole, which serves as an axial ligand for cobalt in vitamin B12. Benzimidazole, in...
-5-acetic acid derivatives. S-8307 and S-8308 have moderate potency
Potency (pharmacology)
In the field of pharmacology, potency is a measure of drug activity expressed in terms of the amount required to produce an effect of given intensity. A highly potent drug evokes a larger response at low concentrations, while a drug of lower potency evokes a small response at low concentrations...
, short duration of action and limited oral bioavailability, however they are selective and competitive AT1 receptor antagonists without partial agonist activity. A group at DuPont postulated that both Ang II and the Takeda leads were bound at the same receptor site. These two substances served as lead compounds for further optimization of AT1 receptor blockers.
Using nuclear magnetic resonance
Nuclear magnetic resonance
Nuclear magnetic resonance is a physical phenomenon in which magnetic nuclei in a magnetic field absorb and re-emit electromagnetic radiation...
studies on the spatial structure of Ang II, scientist at DuPont discovered that the Takeda structures had to be enlarged at a particular position to resemble more closely the much larger peptide Ang II.
Computer modeling was used to compare S-8308 and S-8307 with Ang II and it was seen that Ang II contains two acidic residues near the NH2 terminus. These groups were not mimicked by the Takeda leads and therefore it was hypothesized that acidic functional groups would have to be added to the compounds.
The 4-carboxy-derivative EXP-6155 had a binding activity which was ten-fold greater than that of S-8308 which further strengthened this hypothesis
Hypothesis
A hypothesis is a proposed explanation for a phenomenon. The term derives from the Greek, ὑποτιθέναι – hypotithenai meaning "to put under" or "to suppose". For a hypothesis to be put forward as a scientific hypothesis, the scientific method requires that one can test it...
.
By replacing the 4-carboxy-group with a 2-carboxy-benzamido-moiety the compound EXP-6803 was synthesized. It had highly increased binding affinity but was only active when administered intravenously.
Replacing the 2-carboxy-benzamido-group with a 2-carboxy-phenyl-group created the lipophilic
Lipophilic
Lipophilicity, , refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. These non-polar solvents are themselves lipophilic — the axiom that like dissolves like generally holds true...
biphenyl
Biphenyl
Biphenyl is an organic compound that forms colorless crystals. It has a distinctively pleasant smell. Biphenyl is an aromatic hydrocarbon with a molecular formula 2...
-containing EXP-7711, which exhibited good oral activity but slightly less affinity for the AT1 receptor.
Then the polar
Chemical polarity
In chemistry, polarity refers to a separation of electric charge leading to a molecule or its chemical groups having an electric dipole or multipole moment. Polar molecules interact through dipole–dipole intermolecular forces and hydrogen bonds. Molecular polarity is dependent on the difference in...
carboxyl group was replaced with a more lipophilic tetrazole
Tetrazole
Tetrazoles are a class of synthetic organic heterocyclic compound, consisting of a 5-member ring of four nitrogen and one carbon atom . The simplest is tetrazole itself, CN4H2. They are unknown in nature...
group in order to increase oral bioavailability and duration of action further and the compound thus formed was named losartan. This development took place in 1986 and losartan became the first successful Ang II antagonist
Angiotensin II receptor antagonist
Angiotensin II receptor antagonists, also known as angiotensin receptor blockers , AT1-receptor antagonists or sartans, are a group of pharmaceuticals which modulate the renin-angiotensin-aldosterone system...
drug, approved as such in the United States in 1995 and was marketed by Merck
Merck & Co.
Merck & Co., Inc. , also known as Merck Sharp & Dohme or MSD outside the United States and Canada, is one of the largest pharmaceutical companies in the world. The Merck headquarters is located in Whitehouse Station, New Jersey, an unincorporated area in Readington Township...
.
This development was laborious and expensive work and it is approximated that the process from the Takeda structures to the final substance, losartan, took more than fifty person-years in biological testing and chemical modifications.
Using a different lead optimization from S-8308, eprosartan
Eprosartan
Eprosartan is an angiotensin II receptor antagonist used for the treatment of high blood pressure. It is marketed as Teveten by Abbott Laboratories in the United States.It is marketed as Eprozar by INTAS Pharmaceuticals in the INDIA and by Solvay Pharmaceuticals elsewhere...
was developed by SmithKline Beecham in 1992. Eprosartan does not have a biphenyl-methyl structure but in order to mimic the C-terminal end of Ang II the 5-acetic acid group was replaced with an a-thienylacrylic acid and a 4-carboxy-moiety. Eprosartan is a selective, potent and competitive AT1 antagonist and its binding to AT1 receptors is rapid, reversible, saturable and of high affinity.
Development from losartan to other drugs
Losartan, valsartanValsartan
Valsartan is an angiotensin II receptor antagonist , with particularly high affinity for the type I angiotensin receptor. By blocking the action of angiotensin, valsartan dilates blood vessels and reduces blood pressure...
, candesartan
Candesartan
Candesartan is an angiotensin II receptor antagonist used mainly for the treatment of hypertension. The prodrug candesartan cilexetil is marketed by AstraZeneca and Takeda Pharmaceuticals, commonly under the trade names Blopress, Atacand, Amias, and Ratacand.-Clinical use:As all angiotensin II...
, irbesartan
Irbesartan
Irbesartan is an angiotensin II receptor antagonist used mainly for the treatment of hypertension. Irbesartan was developed by Sanofi Research...
, telmisartan
Telmisartan
Telmisartan is an angiotensin II receptor antagonist used in the management of hypertension. It is marketed under the trade name Micardis , among others.-Administration:...
and olmesartan
Olmesartan
Olmesartan medoxomil is an angiotensin II receptor antagonist used to treat high blood pressure.-Indications:...
all contain a biphenyl-methyl group.
Losartan is partly metabolized to its 5-carboxylic acid
Carboxylic acid
Carboxylic acids are organic acids characterized by the presence of at least one carboxyl group. The general formula of a carboxylic acid is R-COOH, where R is some monovalent functional group...
metabolite
Metabolite
Metabolites are the intermediates and products of metabolism. The term metabolite is usually restricted to small molecules. A primary metabolite is directly involved in normal growth, development, and reproduction. Alcohol is an example of a primary metabolite produced in large-scale by industrial...
EXP 3174, which is a more potent AT1 receptor antagonist than its parent compound and has been a model for the continuing development of several other ARBs.
Valsartan, candesartan and irbesartan were all developed in 1990.
Valsartan, first marketet by Novartis
Novartis
Novartis International AG is a multinational pharmaceutical company based in Basel, Switzerland, ranking number three in sales among the world-wide industry...
, is a nonheterocyclic ARB, where the imidazole of losartan has been replaced by an acyl
Acyl
An acyl group is a functional group derived by the removal of one or more hydroxyl groups from an oxoacid, including inorganic acids.In organic chemistry, the acyl group is usually derived from a carboxylic acid . Therefore, it has the formula RCO-, where R represents an alkyl group that is...
ated amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
.
Irbesartan was developed by Sanofi Research and is longer acting than valsartan and losartan and it has an imidazolinone ring where a carbonyl
Carbonyl
In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups....
group functions as a hydrogen bond
Hydrogen bond
A hydrogen bond is the attractive interaction of a hydrogen atom with an electronegative atom, such as nitrogen, oxygen or fluorine, that comes from another molecule or chemical group. The hydrogen must be covalently bonded to another electronegative atom to create the bond...
acceptor instead of the hydroxymethyl
Hydroxymethyl
Hydroxymethyl in the field of chemistry, particularly in organic chemistry, is the name for a substituent with the structural formula -CH2-OH. The hydroxymethyl group consists of a methylene group connected to a hydroxy group. This makes the hydroxymethyl group an alcohol...
group in losartan. Irbesartan is a non-competitive inhibitor.
Candesartan cilexetil (TCV 116) is a benzimidazole which was developed at Takeda and is an ester
Ester
Esters are chemical compounds derived by reacting an oxoacid with a hydroxyl compound such as an alcohol or phenol. Esters are usually derived from an inorganic acid or organic acid in which at least one -OH group is replaced by an -O-alkyl group, and most commonly from carboxylic acids and...
carbonate
Carbonate
In chemistry, a carbonate is a salt of carbonic acid, characterized by the presence of the carbonate ion, . The name may also mean an ester of carbonic acid, an organic compound containing the carbonate group C2....
prodrug
Prodrug
A prodrug is a pharmacological substance administered in an inactive form. Once administered, the prodrug is metabolised in vivo into an active metabolite, a process termed bioactivation. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and...
. In vivo
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...
, it is rapidly converted to the much more potent corresponding 7-carboxylic acid, candesartan. In the interaction of candesartan with AT1 receptor the carboxyl group of the benzimidazole ring plays an important role. Candesartan and its prodrug have stronger blood pressure lowering effects than EXP 3174 and losartan.
Telmisartan, which was discovered and developed in 1991 by Boehringer Ingelheim, has carboxylic acid as the biphenyl acidic group. It has the longest elimination half-life
Half-life
Half-life, abbreviated t½, is the period of time it takes for the amount of a substance undergoing decay to decrease by half. The name was originally used to describe a characteristic of unstable atoms , but it may apply to any quantity which follows a set-rate decay.The original term, dating to...
of the ARBs or about 24 hours.
Olmesartan medoxomil was developed by Sankyo
Daiichi Sankyo Co.
is a global pharmaceutical company and the second largest pharmaceutical company in Japan. It achieved JPY 970 billion in revenue in 2010 and is currently ranked number 17 in world sales. Its headquarter is based in Tokyo. The company also owns the American biotechnology company Plexxikon, the...
in 1995 and is the newest ARB on the market, marketed in 2002. It is an ester prodrug like candesartan cilexetil. In vivo, the prodrug is completely and rapidly hydrolyzed to the active acid form, olmesartan (RNH-6270). It has a hydroxyisopropyl
Isopropyl
In organic chemistry, isopropyl is a propyl with a group attached to the secondary carbon. If viewed as a functional group an isopropyl is an organic compound with a propyl group attached at its secondary carbon.The bond is therefore on the middle carbon....
group connected to the imidazole ring in addition to the carboxyl group.
Pharmacophore and structure-activity relationship
PharmacophoreThere are three functional groups that are the most important parts for the bioactivity of ARBs, see figure 1 for details.
The first one is the imidazole ring that binds to amino acids in helix 7 (Asn
ASN
ASN may refer to:Organisations:* ASN Bank in the Netherlands* American Society of Nephrology* American Society for Neurochemistry* American Society of Neuroimaging* American Society for Nutrition...
295). The second group is the biphenyl-methyl group that binds to amino acids in both helices 6 and 7 (Phe
PHE
PHE may refer to:* Population Health and Environment , an approach to development that integrates health or family planning with conservation efforts* Paramount Home Entertainment* BitTorrent protocol encryption...
301, Phe
PHE
PHE may refer to:* Population Health and Environment , an approach to development that integrates health or family planning with conservation efforts* Paramount Home Entertainment* BitTorrent protocol encryption...
300, Trp
Tryptophan
Tryptophan is one of the 20 standard amino acids, as well as an essential amino acid in the human diet. It is encoded in the standard genetic code as the codon UGG...
253 and His
Histidine
Histidine Histidine, an essential amino acid, has a positively charged imidazole functional group. It is one of the 22 proteinogenic amino acids. Its codons are CAU and CAC. Histidine was first isolated by German physician Albrecht Kossel in 1896. Histidine is an essential amino acid in humans...
256). The third one is the tetrazole
Tetrazole
Tetrazoles are a class of synthetic organic heterocyclic compound, consisting of a 5-member ring of four nitrogen and one carbon atom . The simplest is tetrazole itself, CN4H2. They are unknown in nature...
group that interacts with amino acids in helices 4 and 5 (Arg
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
167 and Lys
Lysine
Lysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....
199).
The tetrazole group has been successfully replaced by a carboxylic acid group as is the case with telmisartan.
Structure-activity relationship (SAR)
Most of the ARBs have the same pharmacophore
Pharmacophore
thumb|right|300px|An example of a pharmacophore model.A pharmacophore is an abstract description of molecular features which are necessary for molecular recognition of a ligand by a biological macromolecule....
so the difference in their biochemical and physiological effects is mostly due to different substituent
Substituent
In organic chemistry and biochemistry, a substituent is an atom or group of atoms substituted in place of a hydrogen atom on the parent chain of a hydrocarbon...
s. Activity of a drug is dependent of its affinity for the substrate site and the length of time it binds to the site.
Lipophilic substituents like the linear alkyl group at the 2-position on the imidazole ring together with the biphenyl-methyl group, associate with hydrophobic pockets of the receptor. An acidic group like tetrazole, CO2H or NHSO2CF3 at the 1-position of the biphenyl-methyl group will bind to a basic position in the receptor and are required for potent antagonistic
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
activity.
In valsartan, the imidazole ring of losartan has been replaced with an acylated amino acid.
Several substituents have been tried at the 4- and 5- positions on the imidazole ring. The chloro and hydroxymethyl groups connected to these positions in losartan are probably not of much importance in receptor binding since the other ARBs do not possess these functional groups and have comparable or better binding affinities than losartan. Irbesartan has a carbonyl group at the 5-position, functioning as a hydrogen bond acceptor in place of the hydroxymethyl group of losartan, resulting in a longer binding to the receptor.
The structure of eprosartan is the one that differs most from the other ARBs, the usual biphenyl-methyl group has been replaced by a carboxy benzyl
Benzyl
In organic chemistry, benzyl is the term used to describe the substituent or molecular fragment possessing the structure C6H5CH2-. Benzyl features a benzene ring attached to a CH2 group.-Nomenclature:...
group that mimics more closely the phenol
Phenol
Phenol, also known as carbolic acid, phenic acid, is an organic compound with the chemical formula C6H5OH. It is a white crystalline solid. The molecule consists of a phenyl , bonded to a hydroxyl group. It is produced on a large scale as a precursor to many materials and useful compounds...
ic moiety of Tyr
Tyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
4 group of Ang II. This change results in a stronger binding to the receptor but the biochemical and physiological effects are not significantly improved.
Telmisartan has a carboxylic acid at the 2-position of the biphenyl-methyl group and is more potent than the tetrazole analogue.
It has been reported that imidazoles that have hydroxymethyl and carboxy groups at the 4- and 5 position, possessed potent antagonistic activity, caused by the hydrogen bonding and hydrophilicity of the hydroxymethyl group.
It has also been reported that an hydroxy group in the 4-position on the imidazole ring, plays an important role in the binding affinity and compensates for the disadvantage of lipophilicity of the bulky alkyl group.
These results show that a medium-sized hydroxy alkyl group, such as CHMeOH and CMe2OH, is favorable for the substituent of the 4-position on the imidazole ring. Furthermore, the ion
Ion
An ion is an atom or molecule in which the total number of electrons is not equal to the total number of protons, giving it a net positive or negative electrical charge. The name was given by physicist Michael Faraday for the substances that allow a current to pass between electrodes in a...
izable group is favorable for the binding affinity.
Candesartan and olmesartan have the highest affinity for the AT1 receptors, followed by irbesartan and eprosartan. Valsartan, telmisartan and EXP 3174 have similar affinities that are about ten-fold less than that of candesartan. Losartan has the least affinity. ARBs' affinity for the AT2 receptor is generally much lower (or around 10,000 times less) then for the AT1 subtype. Therefore they allow unhindered stimulation of the AT2 receptor.
Drug comparison and pharmacokinetics
| Drug | Biological half-life [h] | Protein binding [%] | Bioavailability [%] | Renal/hepatic clearance Clearance (medicine) In medicine, the clearance is a measurement of the renal excretion ability. Although clearance may also involve other organs than the kidney, it is almost synonymous with renal clearance or renal plasma clearance. Each substance has a specific clearance that depends on its filtration characteristics... [%] |
Food effect | Daily dosage [mg] |
|---|---|---|---|---|---|---|
| Losartan Losartan Losartan is an angiotensin II receptor antagonist drug used mainly to treat high blood pressure . Losartan was the first angiotensin II receptor antagonist to be marketed. Losartan potassium is marketed by Merck & Co. Inc. under the trade name Cozaar... |
2 | 98.7 | 33 | 10/90 | Minimal | 50-100 |
| EXP 3174 | 6-9 | 99.8 | - | 50/50 | - | - |
| Candesartan Candesartan Candesartan is an angiotensin II receptor antagonist used mainly for the treatment of hypertension. The prodrug candesartan cilexetil is marketed by AstraZeneca and Takeda Pharmaceuticals, commonly under the trade names Blopress, Atacand, Amias, and Ratacand.-Clinical use:As all angiotensin II... |
9 | >99 | 15 | 60/40 | No | 4-32 |
| Valsartan Valsartan Valsartan is an angiotensin II receptor antagonist , with particularly high affinity for the type I angiotensin receptor. By blocking the action of angiotensin, valsartan dilates blood vessels and reduces blood pressure... |
6 | 95 | 25 | 30/70 | 40-50% decreased by | 80-320 |
| Irbesartan Irbesartan Irbesartan is an angiotensin II receptor antagonist used mainly for the treatment of hypertension. Irbesartan was developed by Sanofi Research... |
11-15 | 90-95 | 70 | 1/99 | No | 150-300 |
| Telmisartan Telmisartan Telmisartan is an angiotensin II receptor antagonist used in the management of hypertension. It is marketed under the trade name Micardis , among others.-Administration:... |
24 | >99 | 42-58 | 1/99 | No | 40-80 |
| Eprosartan Eprosartan Eprosartan is an angiotensin II receptor antagonist used for the treatment of high blood pressure. It is marketed as Teveten by Abbott Laboratories in the United States.It is marketed as Eprozar by INTAS Pharmaceuticals in the INDIA and by Solvay Pharmaceuticals elsewhere... |
5 | 98 | 13 | 30/70 | No | 400-800 |
| Olmesartan Olmesartan Olmesartan medoxomil is an angiotensin II receptor antagonist used to treat high blood pressure.-Indications:... |
14-16 | >99 | 29 | 40/60 | No | 10-40 |
ARBs have a large therapeutic index
Therapeutic index
The therapeutic index is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes death or toxicity ....
and therefore their (mostly low) oral bioavailability does not appear to be of clinical significance.
As can be seen in table 1, these drugs are highly plasma protein-bound and therefore oral administration once a day should provide sufficient antihypertensive
Antihypertensive
The antihypertensives are a class of drugs that are used to treat hypertension . Evidence suggests that reduction of the blood pressure by 5 mmHg can decrease the risk of stroke by 34%, of ischaemic heart disease by 21%, and reduce the likelihood of dementia, heart failure, and mortality from...
effects.
Around 14 % of orally ingested losartan is metabolized to its 5-carboxylic acid metabolite
Metabolite
Metabolites are the intermediates and products of metabolism. The term metabolite is usually restricted to small molecules. A primary metabolite is directly involved in normal growth, development, and reproduction. Alcohol is an example of a primary metabolite produced in large-scale by industrial...
EXP 3174. As mentioned before, candesartan cilexetil and olmesartan medoxomil are inactive ester prodrugs that are completely hydrolyzed to their active forms by esterases during absorption
Absorption (Pharmacokinetics)
In pharmacology , absorption is the movement of a drug into the bloodstream.Absorption involves several phases...
from the gastrointestinal tract
Gastrointestinal tract
The human gastrointestinal tract refers to the stomach and intestine, and sometimes to all the structures from the mouth to the anus. ....
. These three metabolites are more potent AT1 receptor antagonists than their prodrugs. The other ARBs do not have active metabolites.
All of the ARBs, except for telmisartan and olmesartan, are metabolized in some way by the cytochrome P450 (CYP) enzyme 2C9
CYP2C9
Cytochrome P450 2C9 is a protein that in humans is encoded by the CYP2C9 gene.- Function :CYP2C9 is an important cytochrome P450 enzyme with a major role in the oxidation of both xenobiotic and endogenous compounds. CYP2C9 makes up about 18% of the cytochrome P450 protein in liver microsomes...
, that is found in the human liver. CYP2C9
CYP2C9
Cytochrome P450 2C9 is a protein that in humans is encoded by the CYP2C9 gene.- Function :CYP2C9 is an important cytochrome P450 enzyme with a major role in the oxidation of both xenobiotic and endogenous compounds. CYP2C9 makes up about 18% of the cytochrome P450 protein in liver microsomes...
is for example responsible for the metabolizing of losartan to EXP 3174 and the slow metabolizing of valsartan and candesartan to their inactive metabolites. Telmisartan is, on the other hand, in part metabolized by glucuronidation
Glucuronidation
Glucuronidation is the addition of glucuronic acid to a substrate. Glucuronidation is often involved in xenobiotic metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids...
and olmesartan is excreted as the unchanged drug.
Telmisartan is the only ARB that can cross the blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
and can therefore inhibit centrally mediated effects of Ang II, contributing to even better blood pressure control.
All of the ARBs have the same mechanism of action
Mechanism of action
In pharmacology, the term mechanism of action refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect...
and differences in their potency can be related to their different pharmacokinetic profiles. A few clinical head-to-head comparisons have been made and candesartan, irbesartan and telmisartan appear to be slightly more effective than losartan in lowering blood pressure. This difference may be related to different strengths of activity at the receptor level, such as duration and strength of receptor binding.
ARBs under development
Ketone
In organic chemistry, a ketone is an organic compound with the structure RCR', where R and R' can be a variety of atoms and groups of atoms. It features a carbonyl group bonded to two other carbon atoms. Many ketones are known and many are of great importance in industry and in biology...
moiety (C=O) fused to the imidazole ring (figure 4), and its affinity for the AT1 receptor is about 7 times higher than losartan's. The purpose of the oxo
Ketone
In organic chemistry, a ketone is an organic compound with the structure RCR', where R and R' can be a variety of atoms and groups of atoms. It features a carbonyl group bonded to two other carbon atoms. Many ketones are known and many are of great importance in industry and in biology...
group is similar to that of the carboxylic acid groups on other ARBs.
Other attributes of ARBs are also under investigation, such as the positive effects of telmisartan on lipid
Lipid metabolism
Lipid metabolism refers to the processes that involve the intercourse and degradation of lipids.The types of lipids involved include:* Bile salts* Cholesterols* Eicosanoids* Glycolipids* Ketone bodies* Fatty acids - see also fatty acid metabolism...
and glucose metabolism and losartan's effects of lowering uric acid
Uric acid
Uric acid is a heterocyclic compound of carbon, nitrogen, oxygen, and hydrogen with the formula C5H4N4O3. It forms ions and salts known as urates and acid urates such as ammonium acid urate. Uric acid is created when the body breaks down purine nucleotides. High blood concentrations of uric acid...
levels. Such effects might lead to new indications for these drugs but further research is needed.