The angiotensin receptor blockers (ARBs), also called angiotensin (AT1) receptor antagonists or sartans, are a group of antihypertensive 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, 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 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, the physiologist Robert Tigerstedt and his student, Per Bergman, experimented with rabbits by injecting them with kidney extracts. Their results suggested the kidneys produced a protein, 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; he found the ischaemic kidneys did in fact secrete a chemical that caused vasoconstriction. In 1939, renin was found not to 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 Ang II to harm the heart and kidneys, and 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 those of placebos.Analogue-based Drug Discovery (Optimizing Antihypertensive Therapy by Angiotensin Receptor Blockers; Farsang, C., Fisher, J., p.157-167) Editors; Fischer, J., Ganellin, R. Wiley-VCH 2006.

The angiotensin II receptor The actions of Ang II are mediated by angiotensin receptors, AT1 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.

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 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 vasoconstriction, 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.

Binding pockets

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 Lys199 in the upper part of helix 5 of the receptor; see figure 1 for details. The ionic bridge formed between Lys199 and the carboxyl terminal group of the Phe8 residue of Ang II is most likely stabilized by the Trp253 residue. In addition, Phe259 and Asp263 in transmembrane helix 6 and Lys102 and Ser105 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

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.Goodman & Gilman's The Pharmacological Basis of Therapeutics 11th ed. (Renin and Angiotensin; Jackson E.K., 789-821) Editors; Brunton L.L., Lazo J.S., Parker K.L. New York McGraw Hill 2006.

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.

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, 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 Asp1, Ile5 and Phe8 have been replaced with Ser1, Val5 and Ala8, 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, scientists 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 under the brand name Cozaar.

This development was an extensive program and it is estimated that the process from the Takeda structures to the final substance, losartan, took more than fifty person-years of work in biological testing and chemical modifications. This represents an excellent investment given that a recent study estimated that losartan administration in the European union may reduce health care provision costs by 2.5 billion euro over 3.5 years.

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.

Development from losartan to other drugs Losartan, valsartan, 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 marketed by Novartis, is a nonheterocyclic ARB, where the imidazole of losartan has been replaced by an acylated 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.