Discovery and development of angiotensin receptor blockers/ja: Difference between revisions

Because of [[saralasin]], the first [[angiotensin II antagonist|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]] [[Aspartic acid|Asp]]¹, [[Isoleucine|Ile]]⁵ and [[Phenylalanine|Phe]]⁸ have been replaced with [[Serine|Ser]]¹, [[Valine|Val]]⁵ and [[Alanine|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 Pharmaceutical Company|Takeda]] discovered in 1982 the weak nonpeptide Ang II antagonists S-8307 and S-8308 from a group of 1-[[Benzimidazole|benzylimidazole]]-5-acetic acid derivatives. S-8307 and S-8308 have moderate [[Potency (pharmacology)|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.<br />

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. <br />

Then the [[chemical polarity|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 [[angiotensin II receptor antagonist|Ang II antagonist]] drug, approved as such in the United States in 1995 and was marketed by [[Merck & Co.|Merck]].

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.

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===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 [[Chemical compounds|compound]]

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Valsartan, first marketed by [[Novartis]], is a non[[heterocyclic]] 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 [[Daiichi Sankyo Co.|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 hydroxy[[isopropyl]] group connected to the imidazole ring in addition to the carboxyl group.

===Pharmacophore and structure-activity relationship===

'''Pharmacophore'''<br />

There are three functional groups that are the most important parts for the [[bioactivity]] of ARBs, see figure 1 for details.<br />

The first one is the imidazole ring that binds to amino acids in helix 7 ([[Asparagine|Asn]]²⁹⁵). The second group is the biphenyl-methyl group that binds to amino acids in both helices 6 and 7 ([[Phenylalanine|Phe]]³⁰¹, [[Phenylalanine|Phe]]³⁰⁰, [[Tryptophan|Trp]]²⁵³ and [[Histidine|His]]²⁵⁶). The third one is the [[tetrazole]] group that interacts with amino acids in helices 4 and 5 ([[Arginine|Arg]]¹⁶⁷ and [[Lysine|Lys]]¹⁹⁹). <br />

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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) than for the AT₁ subtype. Therefore, they allow unhindered stimulation of the AT₂ receptor.

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==Drug comparison and pharmacokinetics==

|+ Table 1: Comparison of ARB [[pharmacokinetics]]

! Drug

! Biological half-life [h]

! Protein binding [%]

! Bioavailability [%]

! Renal/hepatic [[Clearance (medicine)|clearance]] [%]

! Food effect

! Daily dosage [mg]

| [[Losartan]]

| Minimal

| [[EXP 3174]]

| [[Candesartan]]

| [[Valsartan]]

| 40-50% decreased by

| [[Irbesartan]]

| No

| [[Telmisartan]]

| No

| [[Eprosartan]]

| No

| [[Olmesartan]]

| No

| colspan="7" style="text-align: center;" |Sources:

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 (pharmacokinetics)|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 valsartan and olmesartan, are metabolized in some way by the [[cytochrome P450]] (CYP) enzyme [[CYP2C9|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.