RETRACTED: Repurposing Angiotensin II Receptor Blockers: Unlocking New Therapeutic Horizons

Drug repurposing (also known as drug repositioning, reprofiling, or re-tasking) is an approach that seeks to find new therapeutic applications for existing approved or investigational drugs beyond their initial intended uses. The Renin-Angiotensin-Aldosterone System (RAAS) is essential for controlling blood pressure and maintaining fluid balance, driving significant structural changes throughout the cardiovascular system, including the heart and blood vessels. As a result, the RAAS is a key therapeutic target for various chronic cardiovascular diseases, ranging from Arterial Hypertension (AH) to Heart Failure (HF). AT1 antagonists can be potentially used for other diseases such as neurodegenerative diseases, cancer, and osteoarthritis.

Introduction

Drug repurposing (repositioning, reprofiling, or re-tasking) is a method used to discover new therapeutic applications for approved or investigational drugs beyond their original medical purposes [1,2]. This approach provides several benefits compared to creating a completely new drug for the same condition. A repurposed drug has an advantage because it has been found safe in preclinical and early human trials [3,4]. As a result, they are less likely to fail due to safety concerns in later efficacy trials. Also, the drug development timeline can be shortened since much of the preclinical testing, safety evaluation, and sometimes formulation work has already been done [5,6]. Finally, the required investment is generally lower, although the amount can vary significantly based on the development stage and process of the repurposing candidate. Combined, these benefits can lead to a quicker and less risky return on investment when developing repurposed drugs, with overall lower costs after considering potential failures. Most importantly repurposed drugs might uncover new targets and biological pathways that could be explored further [7,8].

The Renin-Angiotensin-Aldosterone System (RAAS) is a key regulator of vascular tone and fluid homeostasis. Juxtaglomerular cells release renin which initiates the conversion of angiotensinogen to angiotensin I (Ang I) which is then converted to angiotensin II (Ang II) by ACE and other enzymes [9]. Ang II acts predominantly via angiotensin II type 1 (AT1) receptors to raise blood pressure through vasoconstriction, sympathetic activation, and enhanced sodium retention. Ang II also stimulates aldosterone secretion, further promoting sodium reabsorption [10]. Chronic AT1 activation contributes to vascular inflammation, hypertrophy, and fibrosis. In the opposite direction, AT2 receptor engagement counteracts these effects through vasodilation and natriuresis. Pharmacologic blockade of RAAS offers a therapeutic strategy across multiple cardiovascular and renal conditions [11].

Targeting several pathways at once has proven effective in improving drug performance and combating resistance, particularly in complex diseases. From Alzheimer’s to cancer more and more data show that most of the publicly known diseases are actually multifactorial. The strategy of “one molecule for one drug target”, while it has shown improvements in the lives of a lot people worldwide, is outdated and focus should also be given to the development of Multi-target Directed Ligands (MTDLs) with the simplest example being dual inhibitors. MTDLs are rationally designed to act on several targets and have become a widely accepted approach in drug discovery [12-15].

Thus the focus of this review will be on the study of molecules acting as ARBs and their potential use in other pathological conditions as well as their ability to inhibit multiple molecular targets. Moreover, we will present our laboratory’s work on the development of novel AT1 inhibitors and dual inhibitors for the treatment of multiple diseases. The graphic representation in Figure 1 summarizes the topics covered in this review article.

Figure 1: Graphical representation summarizing the topics that will be analyzed in this review article. Specifically, we will start by listing methodologies in which drug repurposing can be achieved (computationally and experimentally). Then, we will examine how drugs that act as AT1 receptor inhibitors can also exert their effects in other pathologies. Specifically, we will start with the ‘core’ diseases that often coexist in patients taking these drugs (HT; Hypertension, HF; Heart Failure, CKD; Chronic Kidney Disease, ACS; Acute Coronary Syndrome). Then, we will list the diseases in which the RAAS system plays an important role and therefore inhibition of AT1 receptors could help in the treatment of patients as indicated in research (AD; Alzheimer’s Disease, PD; Parkinson’s Disease, RA; Rheumatoid Arthritis, OA; Osteoarthritis, DN; Diabetic Nephropathy, DPN; Diabetic Peripheral Neuropathy, SARS-CoV-2, CS; Candidosis, FS; Fibrosis, TFSSc; Tissue Fibrosis in Systemic Sclerosis, GC; Glioma Cancer, MS; Marfan Syndrome, IBDs; Inflammatory Bowel Diseases, AT; Anxiety, PI; Pathogenic Inflammation, YU; Yet Unknown diseases). Finally, we highlight the work of our laboratory and collaborators towards the design, synthesis and pharmacological evaluation of innovative bioactive compounds, some of which are also multifunctional drugs, for the treatment of hypertension and other diseases. Such compounds include simple molecules, hybrid molecules, sartan derivatives and compounds derived from cheminformatic databases.

Establishing drug repurposing; The example of Sildenafil

The best example of a drug being developed to regulate one condition and ending up more well-known and profitable to another is sildenafil (Viagra). Who would have thought that a drug aimed as an anti-agina agent would end up being used for erectile dysfunction. And so it happened. In 1986, Pfizer established a project team of scientists in Sandwich, UK to develop a selective phosphodiesterase-5 (PDE5) inhibitor and assess its preclinical pharmacological properties. The point was simple; inhibition of PDE5, a selective catalyst in the breakdown of cyclic guanosine monophosphate (cGMP), shall result in the excess of this molecule in the body which will subsequently promote the initiation of a cascade of reactions that ultimately decreases intracellular calcium levels, thereby promoting relaxation of the smooth muscle. Thus, it would result as a mixed dilator of arteries and veins by relaxing vascular smooth muscle, which lowers peripheral vascular resistance and cardiac preload while improving blood flow to ischemic heart tissue. This would have an anti-anginal effect. In 1992, when given doses up to 75 mg three times daily for 10 days, some volunteers experienced side effects such as headaches, flushing, indigestion, and muscle pain. Additionally, some reported penile erections as an unexpected effect. Based on observations and studies of Ignarro, et al. in the early 1990s, where it was found that nitric oxide (NO) acts as the neurotransmitter released from cavernous nerves during sexual arousal, triggering cGMP production and ultimately leading to an erection, clinical trials begun in late 1993 for patients with erectile dysfunction and the rest is history [16].

Sildenafil is the best example of retrospective clinical analysis leading to repurposing (or rescue if the drug had otherwise failed for its primary indication) of a candidate molecule. Typically, a drug repurposing strategy involves three steps before advancing a candidate drug through the development pipeline. The first step is identifying a potential molecule for a specific indication, also known as hypothesis generation. The second step involves assessing the drug’s mechanism of action using preclinical models. The third step is to evaluate the drug’s efficacy in phase II clinical trials, provided there is adequate safety data from phase I studies conducted for the original indication. Among these three steps, the first -accurately identifying the appropriate drug for a specific indication with high confidence- is crucial. This is the stage where modern methods for hypothesis generation can be particularly valuable. These systematic strategies are categorized into computational and experimental approaches, and their combined use is becoming increasingly common to enhance effectiveness. The most frequently employed computational methods include retrospective clinical analyses, molecular docking, signature matching, genetic association studies, pathway mapping, and the use of emerging data sources while experimental approaches such us binding assays to identify relevant target interactions and phenotypic screenings are also employed [2,17,18].

Repurposing Angiotensin II Receptor Blockers (ARBs)

ARBs are used as first-line treatment, with different class indications, in hypertension, heart failure, post-myocardial infarction, chronic kidney disease and for the prevention of cardiovascular events, particularly in individuals with atherosclerotic Coronary Artery Disease (CAD) or type 2 diabetes with at least one organ damage [19].

Hypertension

Elevated blood pressure and Hypertension (HT) are conditions associated with many health issues, especially cardiovascular problems such as heart disease, stroke, and heart failure, with cardiovascular disease being the leading cause of mortality worldwide [20]. From 2025 to 2050, cardiovascular disease prevalence is expected to rise by 90.0% with cardiovascular deaths projected to reach 35.6 million in 2050, up from 20.5 million in 2025 [21,22]. Globally, high blood pressure is responsible for roughly 54% of strokes and 47% of coronary heart disease cases [23].

The major classes of medications for blood pressure control are Angiotensin-Converting Enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), dihydropyridine Calcium Channel Blockers (CCBs), diuretics (thiazides and thiazide-like diuretics), and beta-blockers. According to the European Society of Cardiology guidelines, ACE, ARBs, CCBs and diuretics are recommended as first-line treatment [24,25].

Heart failure

Heart Failure (HF) is a clinical syndrome caused by structural and/or functional heart diseases that increase intracardiac pressure and/or impair cardiac output, affecting approximately 1% - 2% of adults [26,27]. In clinical practice it is well-known that the RAAS system plays a pivotal role in heart failure (HF). Unlike ACE inhibitors, ARBs act downstream by blocking Ang-II from attaching to AT-1 receptors. This is believed to cause Ang-II to bind more to AT-2 receptors, potentially providing greater antifibrotic benefits than ACE inhibitors. However, clinical evidence supporting the effectiveness of ARBs in heart failure patients is less robust compared to that for ACE inhibitors and thus ARBs are recommended in patients intolerance to ACE-I or ARNI (sacubitril/valsartan) [28]. ARNI is a combination of ARBs and neprilysin inhibitors and is recommended in patients with HF who remain symptomatic despite the optimal treatment with ACE-I or ARBs. According to the ESC 2023 guidelines, ARBs are recommended for patients with Heart Failure with Reduced Ejection Fraction (HFrEF) HFrEF (Class I) and Heart Failure with Mid-Range Ejection Fraction (HFmrEF) (Class IIa) who are intolerant to ACE-I and ARNI [29].

Chronic kidney disease

Globally, in 2021, more than 850 million people were affected by kidney disease, approximately twice the number of people living with diabetes (422 million) and 20 times the global prevalence of cancer (42 million). According to the KDIGO (Kidney Disease: Improving Kidney Outcomes) 2024 guidelines, ARBs and ACE, are recommended for people with Chronic Kidney Disease (CKD). Specifically, they are recommended for patients with CKD and severely increased albuminuria (1B), for those with moderately increased albuminuria (2C) and for individuals with moderate-to-severe albuminuria and diabetes (1B) [30].

Acute coronary syndrome

Cardiovascular Disease (CVD) remains the leading cause of death and disability globally and in many cases, Acute Coronary Syndrome (ACS) serves as the initial clinical presentation of CVD [31-33]. Secondary prevention following ACS is essential to improve quality of life and reduce both morbidity and mortality. It should be initiated as soon as possible after the initial event. ARBs are recommended in patients with intolerance of ACE inhibitors after ACS with HF symptoms, Left Ventricular Ejection Fraction < 40%, hypertension and/or CKD [34].

Alzheimer’s disease

Alzheimer’s Disease (AD), is a well-known progressive form of neuronal cell degeneration, which influences older humans and is estimated to affect 139 million people by 2050 [35]. Although AD is a multifactorial disease and the most prevalent type of dementia among older adults, its main cause is still not fully understood. The prevailing theory for the pathophysiology of Alzheimer’s is the amyloid theory. In this theory, the Amyloid Precursor Protein (APP) is being hydrolyzed by β-secretase and γ-secretase to yield the insoluble amyloid-beta (Aβ). This is then accumulated in the brain to finally form the Aβ plaques (senile plaques). Elevated levels of Aβ protein are toxic to mature neurons, leading to the shrinking of dendrites and axons, which eventually results in neuronal death. Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors, designed to decrease Aβ levels, have been tested for many years; however, none have successfully passed clinical trials. In fact one of them (Lanabecestat) was able to lower Cerebrospinal Fluid (CSF) Aβ levels by up to 75%. However, on June 12, 2018, phase II/III trials of Lanabecestat were discontinued due to a lack of efficacy. The same happened to a lot other inhibitors of the same class as they had very small effects on protecting cognitive decline and in some cases worsening it [36-38]. Thus, other molecular targets should be determined for the improvement of Alzheimer’s pathology.

The cerebrovascular aspect of Alzheimer’s disease has frequently been overlooked because of the traditional separation between vascular dementia and AD pathology -an outdated distinction that no longer holds [39,40]. Recently, emerging preclinical and clinical evidence has associated the brain renin angiotensin system (RAS) to AD pathology. Consequently, several elements of the brain RAS -such as angiotensin II type 1 (AT1), angiotensin IV (AT4), and Mas receptors- have been found to be altered in both AD patients and mouse models. Together, the alterations seen in the RAS are believed to play a role in several key neuropathological features of AD, such as neuronal damage, cognitive decline, and vascular problems. Growing evidence has also shown that antihypertensive drugs targeting the RAS -especially Angiotensin Receptor Blockers (ARBs) and Angiotensin-Converting Enzyme Inhibitors (ACEIs)- can help delay the onset and progression of Alzheimer’s disease [41,42]. Moreover, these drugs can have a positive effect on vascular dementia [43].

Parkinson’s disease

Parkinson’s disease (PD) is the most common movement disorder and ranks as the second most widespread neurodegenerative disease. Although Parkinson’s disease (PD) has traditionally been seen mainly as a motor disorder marked by bradykinesia, muscle stiffness, resting tremors, and balance problems, it also includes non-motor symptoms that significantly impact patients’ quality of life. Neuropsychiatric symptoms, such as mood changes, cognitive decline, and psychosis, are the most common among these. Besides reducing quality of life, they also increase the caregiver’s workload and raise the likelihood of institutionalization. Depression is the most common mood disorder, impacting up to 50% of patients as the disease progresses, while anxiety -though frequently occurring alongside depression- has received comparatively less research attention [44]. Evidence suggest that the local nigrostriatal RAAS likely plays a role in regulating dopaminergic neurotransmission, blood flow, and inflammatory responses [45]. The intricate interaction between angiotensin (Ang) and dopamine (DA) relies on the balance of D1, D2, AT1, and AT2 receptors. While the D1 receptor promotes Ang production, the D2 receptor inhibits it. In the same way, AT1 receptors increase DA tone, whereas AT2 receptors decrease it. Notably, PD patients exhibit reduced Ang II binding in the basal ganglia, but it is uncertain if this is a cause or an effect of the neurodegeneration seen in PD. In animal models of PD, neuroprotective effects have been demonstrated with the Angiotensin-Converting Enzyme (ACE) inhibitors captopril and perindopril, as well as the AT1 receptor antagonists losartan, candesartan, and telmisartan. These effects seem to be driven by a decrease in the excessive production of Reactive Oxygen Species (ROS). In a proof-of-concept, randomized, double-blind, crossover study involving PD patients, perindopril enhanced the effects of levodopa without causing dyskinesias. While no clinical trials have yet investigated the neuro protective effects of RAS drugs, a cohort study in hypertensive patients suggested that ACE inhibitors may reduce the risk of developing PD. The RAS represents a promising target for both symptomatic and neuroprotective therapies in PD. Further research involving PD animal models and patients is needed [45-47].

Anxiety

Recent studies indicate that local RAS circuits in the brain influence cardiovascular regulation, anxiety (AT), depression, and memory consolidation, with disruptions associated with Alzheimer’s, Parkinson’s, and other neurodegenerative disorders. Bordet, et al. performed a clinical study where twelve patients were treated with ARBs and 42 with ACE inhibitors (ACEIs). ARB-treated patients had lower anxiety STAI scores than those on ACE-Is or drug-free at baseline and during the follow-up. None of the drugs had an impact on depression scores during the study [48].

Cancer glioma

In cancer therapy Konain, et al. found that AT1 antagonists showcase strong anticancer potential for glioma. Glioma (GC) is the most common and aggressive type of brain tumor and ranks among the deadliest forms of cancer. Among many abnormally expressed genes, the AT1 receptor is reported to be increased in glioma and linked to aggressive tumor characteristics and disease progression. Thus, the research team performed docking studies to eleven FDA approved ARBs and the drug with the highest docking score was selected for in vitro experimentation. in vitro growth inhibitory assays on patient-derived glioma cell lines showed that telmisartan, at a concentration of 45 ± 0.06 μM, could suppress 50% of the malignant glioma U87 cell population, while PCR assays showed that AT1 expression in the untreated sample was high reinforcing the role which exhibits the AT1 receptors on glioma. The results of this study indicate that telmisartan effectively inhibits AT1 expression in glioma cell lines [49].

Pathogenic inflammation

Pathogenic Inflammation (PI) is typically triggered by infections, which stimulate the release of proinflammatory mediators like TNF-α, IL-6, and nitric oxide. While infection is the primary cause of inflammation, it has also been shown that danger signals originating from the host or the environment can provoke sterile inflammation. Inflammasomes are protein complexes within the cytosol that detect pathogen infections and various sterile danger signals, triggering the onset of inflammatory diseases and inflammation-associated diseases such as cardiovascular disease, diabetes and obesity. Of the known inflammasomes, the NLRP3 inflammasome reacts not only to pathogen infections but also to sterile danger signals originating from the host or environment. Therefore, targeting the NLRP3 inflammasome has become a highly desirable drug target to treat a wide range of human diseases. Candesartan is an angiotensin II receptor antagonist widely used as a blood pressure-lowering drug. Lin, et al. showed that candesartan effectively suppressed the NLRP3 inflammasome and pyroptosis in macrophages. Their mechanistic study found that candesartan reduced the expression of NLRP3 and proIL-1β by inhibiting NF-κB activation and decreasing phosphorylation of ERK1/2 and JNK1/2. Additionally, it lessened mitochondrial damage and blocked NLRP3 inflammasome assembly by preventing NLRP3 from binding to PKR, NEK7, and ASC. Furthermore, candesartan partially inhibited IL-1β secretion by promoting autophagy. These findings suggest that candesartan possesses broad anti-inflammatory properties and could potentially be repurposed to treat inflammatory diseases or complications related to NLRP3 [50].

Candidosis

Candidosis (CS) is a common opportunistic infection that can present in various clinical forms, including localized infections in the mouth. Medications targeting the renin-angiotensin system inhibit secreted aspartic proteases produced by Candida albicans. Lara, et al. discovered that these antihypertensive medications could be repurposed to disrupt the metabolism and formation of Candida biofilms, which are commonly linked to clinical candidosis, including oral localized forms like denture stomatitis. Biofilms were exposed to losartan or aliskiren (for comparison) for 24 hours. Both drugs decreased fungal viability at all concentrations [51].

Fibrosis

Research also offers strong support for the anti-fibrotic effects triggered by activating the AT2 receptor of the RAAS system. Stimulation of the AT2 receptor, like when the AT1 receptor is inhibited, has been shown to prevent fibrosis (FS) development in organs such as the lungs, heart, blood vessels, kidneys, pancreas, and skin. In the lungs, AT2 receptor activation even reversed established fibrosis [41,52,53].

Tissue fibrosis in systemic sclerosis

Tissue fibrosis in systemic sclerosis (TFSSc) results from an excessive buildup of extracellular matrix components produced by fibroblasts in skin lesions. Angiotensin II, a vasoconstrictor peptide, is known to promote fibrosis by stimulating extracellular matrix production. Kawaguchi, et al. confirmed this fact and found that abnormal production of Ang II may contribute to tissue fibrosis by causing excessive extracellular matrix production in SSc dermal fibroblasts. This implies that targeting the AT1 receptor with antagonists could offer a new approach for treating tissue fibrosis in SSc patients [54].

Diabetic peripheral neuropathy

Moreover, Iwane, et al. conducted clinical and preclinical studies to test whether pharmacological inhibition of the angiotensin system would prevent Diabetic Peripheral Neuropathy (DPN) accompanying type 2 diabetes mellitus (T2DM). In the clinical study, the enrolled 7464 patients were divided into three groups receiving ACEIs, ARBs and the others (non-ACEI, non-ARB antihypertensives). Bonferroni’s test indicated significantly later DPN development in the ARBs and ACEIs groups than the others group (receiving non-ACEIs, non-ARBs antihypertensives). The results suggests that pharmacological inhibition of the angiotensin system is beneficial to prevent DPN accompanying T2DM [55].

Inflammatory bowel diseases

Inflammatory Bowel Diseases (IBDs) are long-lasting conditions affecting the gastrointestinal tract, characterized by repeated episodes of inflammation. Current treatments for IBD are not curative and fall short in areas such as preventing fibrosis. Medications targeting the Renin–Angiotensin System (RAS) not only lower blood pressure but also have anti-inflammatory and antifibrotic effects, making them a cost-effective option for managing inflammation and fibrosis in the gut. While RAS inhibitors have shown promise in preventing and easing colitis in preclinical studies, evidence from human trials remains limited. According to Salmenkari, et al. retrospective studies of IBD patients treated with ACEIs or ARBs have shown encouraging results, including milder disease progression, fewer hospitalizations, and reduced corticosteroid use. However, prospective studies are necessary to confirm the effectiveness of these promising drugs in treating IBD [56].

Marfan syndrome

Marfan Syndrome (MS) is a genetic disorder typically caused by harmful mutations in the fibrillin-1 (FBN1) gene, leading to gradual enlargement of the aortic root. If left untreated, this aortic dilation can result in life-threatening aortic dissection, occasionally occurring in early adulthood. Based on a meta-analysis by Pitcher, et al. individuals with Marfan syndrome who have not undergone aortic surgery, ARBs reduced the rate of aortic root Z score enlargement by roughly half, even in those also taking β blockers. The impact of β blockers was comparable to that of ARBs. Assuming additive effects, starting combination therapy with both ARBs and β blockers at diagnosis could further reduce the rate of aortic enlargement compared to either treatment alone. If sustained over several years, this approach is expected to delay the need for aortic surgery [57].

SARS-CoV-2

Furthermore, ARBs and ACEIs have been reported to protect hypertensive patients infected with SARS-CoV-2. Renin–Angiotensin System (RAS) inhibitors decrease excess angiotensin II levels while increasing antagonist heptapeptides like alamandine and aspamandine, which help counteract angiotensin II and promote homeostasis and vasodilation. Comprehensive studies have shown that ARBs influence the Renin-Angiotensin System (RAS) by increasing the levels of the ACE2 enzyme more than other hypertension medications. This is especially significant because ACE2 serves as the entry point for SARS-CoV-2 in the nasopharynx, lungs, and heart cells. Their size, polarity, charge, and receptor selectivity make these drugs well-suited for maintaining homeostasis, suggesting they could be promising therapeutic agents against SARS-CoV-2 infection. ACE2 enzyme, which transforms harmful Ang II into the beneficial peptides ANG(1–7) and alamandine, helps maintain balance while simultaneously preventing SARS-CoV-2 from entering through ACE2 [58].

Rheumatoid arthritis

Rheumatoid arthritis (RA) and osteoarthritis (OA) represent the two primary types of inflammatory arthritis. Although RA and OA have distinct mechanisms of development, they share certain similarities. In both cases, ongoing inflammation causes gradual damage to the joints. The Renin-Angiotensin System (RAS) plays a role in the development of both RA and OA [59].

RA is a significant condition that impacts joints by increasing inflammation and leading to periarticular osteopenia. Due to the numerous side effects associated with current RA treatments, finding alternative therapies has become a crucial area of research. A local functional RAAS has been identified in various organs and tissues, such as chondrocytes, synovial fluid, and synovial tissue. ACE and renin concentrations were also higher at the synovial fluid in RA patients. The generated Ang II increases pro-inflammatory cytokines like IL-1, IL-6, and TNF-α, which may play a role in the development of RA. Both experimental and clinical research indicate that RAS inhibitors -especially ARBs, as well as ACE inhibitors and renin inhibitors- play a role in RA by primarily targeting inflammation and oxidative stress [59].

Osteoarthritis

Osteoarthritis (OA) is a painful joint condition characterized by the gradual breakdown of cartilage, resulting in discomfort and reduced movement. Existing diagnostic techniques and the absence of treatments that alter disease progression emphasize the urgent need for new management approaches. Recent studies indicate that the RAAS, especially the effects of Ang II on AT1 and AT2 receptors in synovial tissue, could be crucial in the development of osteoarthritis and rheumatoid arthritis. Excessive activation of AT1R is associated with diseases like hypertension and cardiovascular fibrosis, which have similarities to osteoarthritis. In joint tissues -such as cartilage and synovium- AT1R stimulation by Ang II or inflammatory cytokines like IL-1β triggers the release of pro-inflammatory substances and matrix metalloproteinases (MMPs), speeding up cartilage degradation and worsening joint injury. RAS modulators, including ARBs and ACEIs, are being investigated as possible treatments for osteoarthritis. Kaur, et al. found that inhibition of AT1 receptor shows promise in reducing IL-1β-driven inflammation, extracellular matrix (ECM) breakdown, and chondrocyte death in osteoarthritis, while also promoting ECM production, autophagy, and protection of cartilage cells. These effects are regulated by key transcription factors such as STAT3, NFκB, MAPK, VEGF, and Caspase 3. The results reveal not only the cartilage-protecting benefits of these drugs but also clarify how they reduce inflammation and support chondrocyte survival, providing valuable understanding for potential treatment options [60].

Novel synthetic AT1 antagonists and dual inhibitors

As shown in Table 1, non-peptide molecules with a smaller scaffold than common drugs were synthesized and studied. Thus, (5S)-1-benzylo-5-(1H imidazol-1ylo-methylo-)-2- pyrrolidinone (MM1) was created having with a match simpler synthetic root compared to sartans and a significant antihypertensive activity (71% compared to losartan defined as 100% losartan) [61]. Since these molecules possessed strong inhibitory activity against the AT1 receptor, opened new paths in drug discovery. MMK2 and MMK3 were also synthesized later possessing 80% and 48% antihypertensive activity relative to losartan [62]. The second group consists of derivatives of losartan. Derivative V-8 exhibited an angiotensin II antagonistic effect in vivo (rabbits) that increased with dosage at 2 and 3.5 µmol, similar to the effects seen with losartan. in vitro binding experiments demonstrated that V-8 exhibited strong affinity for the AT1 receptor, specifically within the nanomolar range, similar to losartan (IC₅₀ of V-8: 53.8 ± 6.4 nM; IC₅₀ of losartan: 16.4 ± 1.6 nM) while it did not bind on the AT2 receptor [63,64]. N-substituted 5-butylimidazole derivatives were also synthesized from which compound 5-butyl-1-[[20-(2H-tetrazol-5-yl)biphenyl-4-yl]methyl] imidazole-2-carboxylic acid (30) exhibited higher binding affinity (-log IC₅₀ = 8.46) for the AT1 receptor compared to losartan (-log IC₅₀ = 8.25) [65]. Moreover, N,N’-symmetrically bis-substituted butylimidazole analogs have been synthesized and studied. From these analogues, compounds 11 (also named BV6 and BisA in other citations), 12a, 12b and 14 (also named BisB) showcased higher antagonistic activity (potency) when compared to losartan (11; -logIC₅₀ = 9.46, 12a; -logIC₅₀ = 9.04, 12b; -logIC₅₀ = 8.54, 14; -logIC₅₀ = 8.37 and losartan; -logIC₅₀ = 8.25). Specifically, compound 11 was designed having most of the pharmacological segments of losartan and an additional biphenyltetrazole moiety resulting in increased lipophilicity. These compounds are bis-alkylated imidazole sartan derivatives, called “bisartans”, designed to fill a lipophilic cavity that sartans do not accommodate [65-70]. Since many diseases are actually multifactorial we decided to expand our research of AT1 inhibition to other drug targets as well. As such dual inhibitors were designed, synthesized and studied in silico, in vitro and in vivo. Characteristic examples are quercetin-losartan hybrids for the treatment of Glioblastoma multiforme (GBM). In GBM cells, we showed that this hybrid retains the binding potential of losartan to the AT1R through competition-binding experiments and simultaneously exhibits ROS inhibition and antioxidant capacity similar to native quercetin. Moreover, it appeared that the hybrid can modify the cell cycle distribution in GBM cells, causing cell cycle arrest and triggering cytotoxic effects and inhibits cancer cell proliferation and angiogenesis in primary GBM cultures [71]. Another example is a DHA-Losartan hybrid used as a potent inhibitor of multiple pathway-induced platelet aggregation. The hybrid demonstrated a broad-spectrum antiplatelet effect by inhibiting platelet aggregation via multiple activation pathways, including P2Y12, PAR-1 (Protease-Activated Receptor-1), PAF (Platelet Activating Factor), COX-1 (cyclooxygenase-1), and collagen receptors [72]. We have also scanned compound databases like ChEMBL15 and discovered a lot of molecules that could possibly be used for AT1 inhibition. All analogues bound to the AT1 receptor in a dose-dependent manner, showing significant binding affinities (-log IC₅₀). Specifically, the -log IC₅₀ values for compounds 1, 2, 3, and 4 (Table 1) were 5.66 ± 0.14, 5.68 ± 0.26, 5.59 ± 0.33, and 6.70 ± 0.19, respectively. Notably, compound 4 exhibited a binding affinity to the AT1 receptor that was approximately 10 times higher than the other compounds and closer to that of losartan, which had a value of 8.49 ± 0.18 [73]. All the aforementioned molecules are shown in Table 1.

Table 1: Presentation of the key compounds with significant biological activity that were designed, synthesized and studied computationally and pharmacologically by our research team and collaborators over the years, grouped according to the methodology used to design them. Four major groups are outlined. Group A; small non-peptide molecules, Group B; Sartan Derivatives, Group C; Hybrid Molecules and Group D; Databases.
Structures of Bioactive Compounds	Biological Evaluation
Group A; small non-peptide molecules
	Significant antihypertensive activity (MM1; 71% and MMK2; 80% when compared to losartan defined as 100% losartan) [61,62].
	Antihypertensive activity (MMK3; 48% when compared to losartan defined as 100% losartan) [62].
Group B; Sartan Derivatives
	in vitro binding studies; higher affinity of V8 when compared to losartan for the AT1 receptor (V8; IC50 = 53.8 ± 6.4 nM and losartan; IC50 = 16.4 ± 1.6 nM). V8 is a selective AT1 antagonist [63,64].
	Higher binding affinity of compound 30 compared to losartan (30; -log IC50 = 8.46 and losartan; (-logIC50 = 8.25). importance of carboxy group at the C-2 position [65].
	Compounds 11 (also named BV6 or BisA), 12a and 12b showcase higher antagonistic activity (potency) when compared to losartan (11; -logIC50 = 9.46, 12a; -logIC50 = 9.04, 12b; -logIC50 = 8.54 and losartan; -logIC50 = 8.25). Compound’s 11 elevated docking score for the AT1 receptor is due to a greater number of hydrophobic interactions compared to losartan [65-70].
	Compound 14 (also named BisB) showcases higher antagonistic activity (potency) when compared to losartan (14; -logIC50 = 8.37 and losartan; -logIC50 = 8.25) [65-70].
Group C; Hybrid Molecules
	Quercetin-Losartan Hybrid retains the binding potential of losartan to the AT1R, exhibits ROS inhibition and antioxidant capacity similar to native quercetin, modifies the cell cycle distribution in GBM cells and inhibits cancer cell proliferation and angiogenesis in primary GBM cultures [71].
	DHA-Losartan; potent inhibitor of multiple pathway-induced platelet aggregation, like P2Y12, PAR-1 (Protease-Activated Receptor-1), PAF (Platelet Activating Factor), COX-1 (cyclooxygenase-1), and collagen receptors [72].
Group D; Databases
	Compound 1 shows good binding affinity for the AT1 receptor but not better than losartan (1; -logIC50 = 5.66 ± 0.14 and losartan; -logIC50 = 8.49 ± 0.18) [73].
	Compound 2 shows good binding affinity for the AT1 receptor but, also no better than losartan (2; -logIC50 = 5.68 ± 0.26 and losartan; -logIC50 = 8.49 ± 0.18) [73].
	Compound 3 shows worst binding affinity for the AT1 receptor compared to 1 and 2 and no better than losartan (1; -logIC50 = 5.59 ± 0.33 and losartan; -logIC50 = 8.49 ± 0.18) [73].
	Compound 4 has 10-fold higher binding affinity for the AT1 receptor compared to 1, 2 and 3 but not better than losartan (1; -logIC50 = 6.70 ± 0.19 and losartan; -logIC50 = 8.49 ± 0.18) [73].

The compounds we have synthesized along with our collaborators have been organized into 4 separate groups and can be seen in Figure 2.

Figure 2: Schematic representation of the compounds designed, synthesized and studied in silico, in vitro and in vivo by our laboratory and collaborators over the years. All of them can be separated into 4 major groups; 1) molecules discovered and designed with the contribution of databases, 2) molecules that are sartan derivatives, 3) hybrid molecules and 4) molecules with a simple structure that satisfactorily inhibit AT1 receptors.

Bisartans: Second- generation non-peptide mimetics of Ang II as pan antiviral drugs

Second- generation ARB bisartans discovered in our laboratories [65-70], in which both imidazole nitrogens are substituted with biphenyltetrazole, exhibit remarkable affinity and strong binding to the catalytic sites of viruses SARS-CoV-2, Influenza, and Respiratory Syncytial Viruses rendering them potential pan-antiviral drugs [74]. This property may derive from the dual interaction of both warhead negative tetrazoles with positive arginines which trigger infections [67,75]. Pioneer research earlier on the design and synthesis of losartan analogs has led to the discovery of a new class of ARBs where the imidazole substituents, i.e., the butyl and hydroxyl methylene groups at positions 2 and 4, respectively, are at reversed positions compared to losartan [63-65]. These analogs were the basis to further develop bisalkylated derivatives which symmetrically bear two biphenyl tetrazole groups on the two imidazole nitrogens, called bisartans, with notable properties relevant to hypertension and coronavirus 2019 therapies [65-70].

The use of benzimidazole as a scaffold instead of imidazole and bis biphenyl tetrazole alkylation resulted in the development of new bisartans, which exhibited the unique binding affinities due to tetrazole and increased aromaticity [76]. Interaction of aromatic phenyl groups with arginines, as between ARBs and AT1R R167, has been previously reported as a dominant binding factor due to the π-π electron interactions [77]. Arginine is a key amino acid in disease, and arginine blockers, like ARBs or bisartans containing warhead anionic tetrazoles, are emerging as promising pharmaceutics to battle arginine- based viruses and other diseases. The unique and fascinating properties of tetrazole have recently received significant attention in medicinal chemistry for innovative therapies [78,79].

Conclusion

The Renin-Angiotensin-Aldosterone System (RAAS) plays a crucial role in regulating vascular tone and maintaining fluid balance. In the classical pathway prorenin is converted into renin in the kidneys. Afterwards, renin converts angiotensinogen into angiotensin I (Ang I) which is metabolized to angiotensin II (Ang II) and binds to angiotensin II type 1 (AT1) receptors resulting in elevated blood pressure through vasoconstriction, sympathetic activation, and enhanced sodium retention. Thus, AT1 antagonists are used in the treatment for hypertension and cardiovascular diseases like heart failure, chronic kidney disease and acute coronary syndrome. Due to the fact that this system is a highly complex hormonal cascade that spans multiple organs and cell types it becomes evident that it plays an important role in the occurrence of multiple diseases when it malfunctions. Drug repurposing is a convenient way of utilizing existing drugs, such as angiotensin II receptor blockers (ARBs) towards the therapy of different diseases. In this review, we have outlined the importance of drug repurposing (repositioning) for AT1 antagonists and in some cases ACE inhibitors (ACEIs). Examples are given for neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases, anxiety, certain types of cancer like glioma, etc. These studies are very promising and, in combination with rational drug design along with the creation of hybrid molecules for the selective inhibition of multiple targets, many new possibilities arise towards the resolution of various pathological conditions. For example, the design of a compound which processes the inhibitory activity of losartan (AT1 inhibitor) and Lanabecestat (a potent BACE1 inhibitor) could open new paths in the treatment of Alzheimer’s disease. Finally, we discuss our own research on novel AT1 antagonists. These molecules range from small non-peptide compounds to sartan derivatives and hybrid molecules. It becomes evident that the possibilities for ARBs utilization towards the synthesis or improvement of already existing compounds are many and our research should head towards this goal.

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