Rational Design and Synthesis of AT1R Antagonists

molecules Review Rational Design and Synthesis of AT1R Antagonists Nikitas Georgiou 1,†, Vasileios K. Gkalpinos 2,†, Spyridon D. Katsakos 2,†, Stamatia Vassiliou 1,*, Andreas G. Tzakos 2,3,* and Thomas Mavromoustakos 1,* 1 Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis Zografou, 15771 Athens, Greece; [email protected] 2 Department of Chemistry, Section of Organic Chemistry and Biochemistry, University of Ioannina, 45110 Ioannina, Greece; [email protected] (V.K.G.); [email protected] (S.D.K.) 3 University Research Center of Ioannina (URCI), Institute of Materials Science and Computing, 45110 Ioannina, Greece * Correspondence: [email protected] (S.V.); [email protected] (A.G.T.); [email protected] (T.M.) † These authors contributed equally to this work. Abstract: Hypertension is one of the most common diseases nowadays and is still the major cause of premature death despite of the continuous discovery of novel therapeutics. The discovery of the Renin Angiotensin System (RAS) unveiled a path to develop efficient drugs to fruitfully combat hypertension. Several compounds that prevent the Angiotensin II hormone from binding and activating the AT1R, named sartans, have been developed. Herein, we report a comprehensive review of the synthetic paths followed for the development of different sartans since the discovery of the first sartan, Losartan. Keywords: sartans; hypertension; AT1R; Angiotensin II; rational design Citation: Georgiou, N.; Gkalpinos, V.K.; Katsakos, S.D.; Vassiliou, S.; Tzakos, A.G.; Mavromoustakos, T. Rational Design and Synthesis of 1. Introduction AT1R Antagonists. Molecules 2021, 26, Hypertension is a medical condition where the blood pressure in the arteries is ele- 2927. https://doi.org/10.3390/ vated. However, even if one does not exhibit symptoms, long-term high blood pressure is molecules26102927 the major risk factor for numerous pathologies, such as stroke or heart failure. Angiotensin II (AII) receptor blockers are a class of molecules that act in the Renin Angiotensin System Academic Editors: Brullo Chiara (RAS) through binding to the AT1 receptor (Angiotensin II receptor type 1, AT1R) and and Gyorgy M. Keseru preventing its activity. AT1R is a G-protein-coupled receptor that is responsible for AII pathophysiological actions [1]. Received: 24 March 2021 Sartans are a class of therapeutics that act in RAS through AII binding to the AT1R. Accepted: 10 May 2021 The first of this class of molecules was losartan, which was approved by the FDA in 1995, Published: 14 May 2021 and it was released to the market in April 1995. Specifically, Duncia et al. published the discovery of DuP753 (losartan), a potent, orally active nonpeptide Angiotensin II (AII) Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in receptor antagonist (see Figure1) and other derivatives. Their aim was to develop a peptide- published maps and institutional affil- mimetic molecule based on structural features of the AII peptide, which are responsible for iations. its biological activity. This is a similar approach to that followed by Cushman and Ondetti that led to the discovery of captopril [2,3]. The first, important, evidence that triggered the discovery of losartan was the fact that the C-terminal amino acids of AII are responsible for binding to the AT1R. The C-terminal tetrapeptide (AII 5–8) has a very low binding affinity to the AT1R, but at high concentration Copyright: © 2021 by the authors. displaces [125I]-AII from the receptor. The first hypothesis was that both AII and the Licensee MDPI, Basel, Switzerland. This article is an open access article lead molecules of the Takeda Pharmaceutical Company Limited (imidazole-5-acetic acid distributed under the terms and derivatives) [4], bind to the same receptor site. They hypothesized that the poor binding conditions of the Creative Commons affinity of the Takeda’s molecules was due to their small size and partial resemblance to Attribution (CC BY) license (https:// the AII. They overlapped compound 3 (Figure1) with a conformer of AII in the following creativecommons.org/licenses/by/ way: (a) the carboxylic acid group of 3 was aligned with the C-terminal carboxylic acid of 4.0/). AII; (b) the imidazole of 3 was aligned with the imidazole His6 of AII; (c) the lipophilic Molecules 2021, 26, 2927. https://doi.org/10.3390/molecules26102927 https://www.mdpi.com/journal/molecules Molecules 2021, 26, x FOR PEER REVIEW 2 of 20 Molecules 2021, 26, 2927 2 of 18 following way: (a) the carboxylic acid group of 3 was aligned with the C-terminal carboxylic acid of AII; (b) the imidazole of 3 was aligned with the imidazole His6 of AII; (c) the n-butyllipophilic side n-butyl chainof side3 was chain pointed of 3 was into pointed an area into where an thearea Ile5 where residue’s the Ile5 aliphatic residue’s side ali- chain resides;phatic side (d) the chain benzyl resides; group (d) the was benzyl pointing grou towardp was pointing the N terminus toward the of AII. N terminus The para of position AII. ofThe the para benzyl position group of seemedthe benzyl to begroup the seemed ideal place to be to the attach ideal aplace functional to attach group a functional to enlarge thesegroup compounds to enlarge these and allow compounds them to and better allow mimic them AII.to better As AII mimic contains AII. As two AII acidic contains groups, thetwoβ -COOHacidic groups, of Asp the and β-COOH the OH of of Asp Tyr and they the introduced OH of Tyr they a second introduced acidic a functional second acidic group, namely,functional a carboxylic group, namely, acidinto a carboxylic the para acid position into the of para the phenyl position ring of the of 3phenyl. Losartans’ ring of active 3. metaboliteLosartans’ isactive EXP metabolite 3174 that isis responsibleEXP 3174 that for is the responsible mapped for antihypertensive the mapped antihyperten- activity [5,6]. siveLosartan activity [5,6]. is commercially available and it was the first orally active drug, approved by theLosartan FDA for is the commercially treatment ofavailable hypertension. and it was The the production first orally ofactive losartan drug, was approved followed by the FDA for the treatment of hypertension. The production of losartan was followed by seven other commercially available derivatives that were classified as sartans. It is of by seven other commercially available derivatives that were classified as sartans. It is of interest to note that losartan was designed and developed based solely on the solution interest to note that losartan was designed and developed based solely on the solution conformation of the peptide hormone AII which was further modified by rational design conformation of the peptide hormone AII which was further modified by rational design steps. At the time there were no crystallographic data about its structure, which had yet steps. At the time there were no crystallographic data about its structure, which had yet toto be be crystallized crystallized [[7]7] asas alsoalso of the AT1R. AT1R. Although Although numerous numerous conformations conformations have have been been publishedpublished inin differentdifferent environments environments for for AII AII [5–18] [5–18 the] theputative putative bioactive bioactive conformation conformation of ofAII AII has has been been recently recently unveiled unveiled through through its bindin its bindingg to the AT1R to the [7,10,19,20]. AT1R [7,10 In,19 this,20 article]. In this articlewe will we focus will on focus the onmajor the synthetic major synthetic routes followed routes followedto commercially to commercially available sartans available sartans(Figure (Figure 2). 2). Molecules 2021, 26, x FOR PEER REVIEW 3 of 20 FigureFigure 1. 1.Design Design effortsefforts thatthat led to the the development development of of losartan. losartan. Figure 2. 2. StructuresStructures of of commercially commercially available available sartans. sartans. 2. Synthetic Routes of Different Sartans 2.1. Synthetic Routes of Losartan One common structural characteristic of the commercially AT1R antagonists is that they contain an acidic group such as carboxylate or tetrazole or 5-oxo-1,2,4-oxadiazole ring. Tetrazole and 5-oxo-1,2,4-oxadiazole ring groups are prepared from nitrile group and are bioisosteric. They also retain a more favorable pharmacological effect, pharmacokinetic profile and they are metabolically more stable compared to carboxylate group. The replacement of a functional group by another that modifies beneficially the pharmaceutical profile of a compound is a fundamental medicinal chemistry strategy known as isosteric or bioisosteric replacement [21–25]. It has been claimed that the substitution of the tetrazole ring in candesartan by the structurally identical 5-oxo-1,2,4-oxadiazole ring on azilsartan has led to unique pharmacological properties [26]. In an efficient and green synthetic route to losartan, Shangxia et al. [27] in the last step converted the nitrile derivative to tetrazole ring. Their synthetic methodology is de- void of hazardous chemicals like hydrogen chloride and ammonia, making the process convenient and eco-friendly (Scheme 1, [27]). Molecules 2021, 26, 2927 3 of 18 2. Synthetic Routes of Different Sartans 2.1. Synthetic Routes of Losartan One common structural characteristic of the commercially AT1R antagonists is that they contain an acidic group such as carboxylate or tetrazole or 5-oxo-1,2,4-oxadiazole ring. Tetrazole and 5-oxo-1,2,4-oxadiazole ring groups are prepared from nitrile group and are bioisosteric. They also retain a more favorable pharmacological effect, pharmacokinetic profile and they are metabolically more stable compared to carboxylate group. The replacement of a functional group by another that modifies beneficially the pharmaceutical profile of a compound is a fundamental medicinal chemistry strategy known as isosteric or bioisosteric replacement [21–25]. It has been claimed that the substitution of the tetrazole ring in candesartan by the structurally identical 5-oxo-1,2,4-oxadiazole ring on azilsartan has led to unique pharmacological properties [26].

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