New Perspectives for Antihypertensive Sartans as Components of Co-crystals and Co-amorphous Solids with Improved Properties and Multipurpose Activity.

Sartans (angiotensin II receptor blockers, ARBs), drugs used in the treatment of hypertension, play a principal role in addressing the global health challenge of hypertension. In the past three years, their potential use has expanded to include the possibility of their application in the treatment of COVID-19 and neurodegenerative diseases (80 clinical studies worldwide). However, their therapeutic efficacy is limited by their poor solubility and bioavailability, prompting the need for innovative approaches to improve their pharmaceutical properties. This review discusses methods of co-crystallization and co-amorphization of sartans with nonpolymeric, low molecular, and stabilizing co-formers, as a promising strategy to synthesize new multipurpose drugs with enhanced pharmaceutical properties. The solid-state forms have demonstrated the potential to address the poor solubility limitations of conventional sartan formulations and offer new opportunities to develop dual-active drugs with broader therapeutic applications. The review includes an in-depth analysis of the co-crystal and co-amorphous forms of sartans, including their properties, possible applications, and the impact of synthetic methods on their pharmacokinetic properties. By shedding light on the solid forms of sartans, this article provides valuable insights into their potential as improved drug formulations. Moreover, this review may serve as a valuable resource for designing similar solid forms of sartans and other drugs, fostering further advances in pharmaceutical research and drug development.

Design, synthesis and biological evaluation of novel indole-3-carboxylic acid derivatives with antihypertensive activity.

Molecular design, synthesis, in vitro and in vivo studies of novel derivatives of indole-3-carboxylic acid new series of angiotensin II receptor 1 antagonists is presented. Radioligand binding studies using [125I]-angiotensin II displayed that new derivatives of indole-3-carboxylic acid have a high nanomolar affinity for the angiotensin II receptor (AT1 subtype) on a par with the known pharmaceuticals such as losartan. Biological studies of synthesized compounds in spontaneously hypertensive rats have demonstrated that compounds can lower blood pressure when administered orally. Maximum the decrease in blood pressure was 48 mm Hg with oral administration of 10 mg/kg and antihypertensive effect was observed for 24 h, which is superior to losartan.

Receptor Interactions of Angiotensin II and Angiotensin Receptor Blockers-Relevance to COVID-19.

Angiotensin II (Ang II) may contain a charge relay system (CRS) involving Tyr/His/carboxylate, which creates a tyrosinate anion for receptor activation. Energy calculations were carried out to determine the preferred geometry for the CRS in the presence and absence of the Arg guanidino group occupying position 2 of Ang II. These findings suggest that Tyr is preferred over His for bearing the negative charge and that the CRS is stabilized by the guanidino group. Recent crystallography studies provided details of the binding of nonpeptide angiotensin receptor blockers (ARBs) to the Ang II type 1 (AT1) receptor, and these insights were applied to Ang II. A model of binding and receptor activation that explains the surmountable and insurmountable effects of Ang II analogues sarmesin and sarilesin, respectively, was developed and enabled the discovery of a new generation of ARBs called bisartans. Finally, we determined the ability of the bisartan BV6(TFA) to act as a potential ARB, demonstrating similar effects to candesartan, by reducing vasoconstriction of rabbit iliac arteries in response to cumulative doses of Ang II. Recent clinical studies have shown that Ang II receptor blockers have protective effects in hypertensive patients infected with SARS-CoV-2. Therefore, the usage of ARBS to block the AT1 receptor preventing the binding of toxic angiotensin implicated in the storm of cytokines in SARS-CoV-2 is a target treatment and opens new avenues for disease therapy.

Angiotensin II receptor type 1 - An update on structure, expression and pathology.

The AT1 receptor, a major effector of the renin-angiotensin system, has been extensively studied in the context of cardiovascular and renal disease. Moreover, angiotensin receptor blockers, sartans, are among the most frequently prescribed drugs for the treatment of hypertension, chronic heart failure and chronic kidney disease. However, precise molecular insights into the structure of this important drug target have not been available until recently. In this context, seminal studies have now revealed exciting new insights into the structure and biased signaling of the receptor and may thus foster the development of novel therapeutic approaches to enhance the efficacy of pharmacological angiotensin receptor antagonism or to enable therapeutic induction of biased receptor activity. In this review, we will therefore highlight these and other seminal publications to summarize the current understanding of the tertiary structure, ligand binding properties and downstream signal transduction of the AT1 receptor.

Evaluation of Drug Dissolution Rate in Co-amorphous and Co-crystal Binary Drug Delivery Systems by Thermodynamic and Kinetic Methods.

In order to better explain and predict the dissolution characteristics of binary drug delivery systems (BDDSs), the dissolution behaviors of co-crystal (CC) and co-amorphous (CA) systems of sacubitril (SCB) and valsartan (VST) were evaluated in vitro and in vivo by thermodynamic and kinetic methods. The CCs of SCB and VST were prepared into a CA state through rotary evaporation. Solid-state properties were systematically evaluated. Herein, based on the results from previous studies of single-phase systems, we used thermodynamic methods to evaluate the increase in drug dissolution rate after BDDSs change from the crystalline to the amorphous state. After comparing the predicted and measured dissolution rate enhancement of the CC and CA systems, this paper attempts to explain the dissolution rate characteristics of the BDDSs. We then evaluated the bioavailability of two BDDSs in beagle dogs to confirm that there was no discrepancy in vivo with the results obtained in vitro. The results exhibited that there is strong intermolecular interaction between SCB and VST and good physical stability for the CA system. Compared with the CC, the bioavailability of SCB and VST in the CA system increased by 313.9% and 130.5%, respectively. The predicted dissolution rate ratio between CC and CA systems and their actual intrinsic dissolution rates differed by only a factor of 2.5, demonstrating the good correlation between the predicted and measured values. In the future, this method could be expanded to a variety of new samples and exciting drug prospects.

Study on the Formation of Antihypertensive Twin Drugs by Caffeic Acid and Ferulic Acid with Telmisartan.

PURPOSE: This study aimed to synthesize twin drugs from cinnamic acid compounds, caffeic acid (CFA) and ferulic acid (FLA), which can antagonize endothelin-1 (ET-1) with telmisartan through ester bonds. Moreover, the antihypertensive effect of telmisartan and its influence on blood pressure variability (BPV) were enhanced, and the bioavailability of caffeic acid and ferulic acid was improved. METHODS: Six twin drugs, which were the target compounds, were synthesized. Hypertensive rats (SHR) and conscious sinoaortic-denervated (SAD) rats were spontaneously used as models for pharmacodynamic research to study the antihypertensive efficacy of these twin drugs. Wistar rats were employed as pharmacokinetic research models to investigate the pharmacokinetics of the target compounds via intragastric administration. Cellular pharmacodynamic research was also conducted on the antagonistic action on Ang II-AT1, ETA and ETB receptor. RESULTS: Compound 1a was determined as the best antihypertensive twin drug and thus was further studied for its effect on BPV. Compared with that of telmisartan, the antihypertensive effect of compound 1a was improved (p<0.05), and the BPV was reduced (p<0.05). The bioavailability of caffeic acid and ferulic acid after hydrolysis from twin drugs could be increased to varying degrees, and the differences of the main pharmacokinetic parameters among the different forms of caffeic acid and ferulic acid were statistically significant (p<0.05 or p<0.01). Compound 1a had the best antagonistic effect on the Ang II-AT1 receptor. However, the IC50 of Lps-2 was still two orders of magnitude higher than that of the positive drug telmisartan. Hence, the twin drugs worked by metabolizing and regenerating telmisartan and caffeic acid or ferulic acid in the body. CONCLUSION: The synthesized twin drugs improved telmisartan's antihypertensive effects, significantly decreased BPV in SAD rats and increased the bioavailability of caffeic acid and ferulic acid. This study serves as a basis for the development of new angiotensin receptor blocker (ARB) in the future and a reference for the development of new drugs to antagonize ET-1.

Pharmacological Heart Failure Therapy in Children: Focus on Inotropic Support.

Pediatric heart failure is a clinical syndrome, which needs to be distinctly defined and the pathophysiological consequences considered. Pharmacological treatment depends on the disease- and age-specific myocardial characteristics. Acute and chronic low cardiac output is the result of an inadequate heart rate (rhythm), myocardial contractility, preload and afterload, and also ventriculo-ventricular interaction, synchrony, atrio-ventricular and ventricular-arterial coupling. The treatment of choice is curing the cause of heart failure, if possible.Acute HF therapy is still based to the use of catecholamines and inodilators. The cornerstone of chronic HF treatment consists of blocking the endogenous, neuro-humoral axis, in particular the adrenergic and renin-angiotensin-aldosterone system.Before neprilysin inhibitors are used in young children, their potential side-effect for inducing Alzheimer disease needs to be clarified. The focus of the current review is put on the differential use of the inotropic drugs as epinephrine, norepinephrine, dopamine and dobutamine, and also the inodilators milrinone and levosimendan. Considering effects and side-effects of any cardiac stimulating treatment strategy, co-medication with ß-blockers, angiotensin converting inhibitors (ACEIs), angiotensin blockers (ARBs) and mineralocorticoid receptor antagonists (MRAs) is not a contradiction, but a senseful measure, even still during the acute inotropic treatment.Missing sophisticated clinical trials using accurate entry criteria and clinically relevant endpoints, there is especially in cardiovascular diagnosis and treatment of young children a compromise of evidence-based versus pathophysiology-based procedures. But based on the pharmacological and pathophysiological knowledge a hypothesis-driven individualized treatment is already currently possible and therefore indicated.

Drug Treatment of Hypertension: Focus on Vascular Health.

Hypertension, the most common preventable risk factor for cardiovascular disease and death, is a growing health burden. Serious cardiovascular complications result from target organ damage including cerebrovascular disease, heart failure, ischaemic heart disease and renal failure. While many systems contribute to blood pressure (BP) elevation, the vascular system is particularly important because vascular dysfunction is a cause and consequence of hypertension. Hypertension is characterised by a vascular phenotype of endothelial dysfunction, arterial remodelling, vascular inflammation and increased stiffness. Antihypertensive drugs that influence vascular changes associated with high BP have greater efficacy for reducing cardiovascular risk than drugs that reduce BP, but have little or no effect on the adverse vascular phenotype. Angiotensin converting enzyme ACE inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) improve endothelial function and prevent vascular remodelling. Calcium channel blockers also improve endothelial function, although to a lesser extent than ACEIs and ARBs. Mineralocorticoid receptor blockers improve endothelial function and reduce arterial stiffness, and have recently become more established as antihypertensive drugs. Lifestyle factors are essential in preventing the adverse vascular changes associated with high BP and reducing associated cardiovascular risk. Clinicians and scientists should incorporate these factors into treatment decisions for patients with high BP, as well as in the development of new antihypertensive drugs that promote vascular health.

Exploring new scaffolds for angiotensin II receptor antagonism.

Nowadays, AT1 receptor (AT1R) antagonists (ARBs) constitute the one of the most prevalent classes of antihypertensive drugs that modulate the renin-angiotensin system (RAS). Their main uses include also treatment of diabetic nephropathy (kidney damage due to diabetes) and congestive heart failure. Towards this direction, our study has been focused on the discovery of novel agents bearing different scaffolds which may evolve as a new class of AT1 receptor antagonists. To fulfill this aim, a combination of computational approaches and biological assays were implemented. Particularly, a pharmacophore model was established and served as a 3D search query to screen the ChEMBL15 database. The reliability and accuracy of virtual screening results were improved by using molecular docking studies. In total, 4 compounds with completely diverse chemical scaffolds from potential ARBs, were picked and tested for their binding affinity to AT1 receptor. Results revealed high nanomolar to micromolar affinity (IC50) for all the compounds. Especially, compound 4 exhibited a binding affinity of 199nM. Molecular dynamics simulations were utilized in an effort to provide a molecular basis of their binding to AT1R in accordance to their biological activities.

Spotlight on valsartan-sacubitril fixed-dose combination for heart failure: the evidence to date.

Heart failure is a global problem with elevated prevalence, and it is associated with substantial cardiovascular morbidity and mortality. Treating heart-failure patients has been a very challenging task. This review highlights the main pharmacological developments in the field of heart failure with reduced ejection fraction, giving emphasis to a drug that has a dual-acting inhibition of the neprilysin and renin-angiotensin-aldosterone system. Neprilysin is an enzyme that participates in the breakdown of biologically active natriuretic peptides and several other vasoactive compounds. The inhibition of neprilysin has been a therapeutic target for several drugs tested in cardiovascular disease, mainly for heart failure and/or hypertension. However, side effects and a lack of efficacy led to discontinuation of their development. LCZ696 is a first-in-class neprilysin- and angiotensin-receptor inhibitor that has been developed for use in heart failure. This drug is composed of two molecular moieties in a single crystalline complex: a neprilysin-inhibitor prodrug (sacubitril) and the angiotensin-receptor blocker (valsartan). The PARADIGM-HF trial demonstrated that this drug was superior to an angiotensin-converting enzyme inhibitor (enalapril) in reducing mortality in patients with heart failure with reduced ejection fraction. The ability to block the angiotensin receptor and augment the endogenous natriuretic peptide system provides a distinctive mechanism of action in cardiovascular disease.

Fimasartan for independent reduction of blood pressure variability in mild-to-moderate hypertension.

BACKGROUND: The angiotensin receptor antagonist fimasartan lowered blood pressure (BP) in a previous large population study. The purpose of this study was to evaluate whether fimasartan treatment for 3 months affects clinical and home BP variability in addition to reducing BP. METHODS: The study enrolled 1,396 patients (mean age 56.2±10.0 years; males 53.6%) with mild-to-moderate hypertension who had a complete set of home BP measurements (morning and evening) and metabolic risk evaluation. During the 3 months of study, fimasartan alone was used to control BP at a daily dose of 30-120 mg. Clinical and home BP measurements were performed before and after the 3-month treatment. BP variability included beat-to-beat variability (clinical) and day-to-day variability (home). RESULTS: Fimasartan reduced BP after 3 months of treatment. The average reduction of clinical systolic BP (c-SBP) was 15.08±18.36 mmHg (P<0.0001), and the average reduction of morning home SBP (m-SBP) was 11.49±19.33 mmHg (P<0.0001). Beat-to-beat variability as standard deviation (SD) of c-SBP was reduced from 4.56±3.22 to 4.24±3.11 mmHg (P=0.0026). Day-to-day variability as SD of m-SBP was reduced from 7.92±6.74 to 6.95±4.97 mmHg (P<0.0001). Multiple regression analysis revealed an independent association between the change in the SD of c-SBP and the change in c-SBP (P=0.0268) and, similarly, between the change in the SD of m-SBP and the change in m-SBP (P=0.0258), after adjusting for age, sex, body mass index, and change in mean BP. CONCLUSION: This study indicated that 3 months of fimasartan treatment reduced day-to-day BP variability independent of BP reduction in patients with hypertension.

N-Phenyl indole derivatives as AT1 antagonists with anti-hypertension activities: Design, synthesis and biological evaluation.

The design, synthesis, in vitro and in vivo evaluation of 6-substituted benzimidazole with 1, 4-disubsituted or 1, 5-disubsituted indole derivatives as novel angiotensin II receptor antagonists are outlined. Radioligand binding assays showed that several 6-substituted benzimidazole derivatives displayed high affinities binding to the angiotensin II type 1 receptor at the same order of magnitude to telmisartan. The biological evaluation on spontaneously hypertensive rats showed that 2-[4-[[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)benzimidazole-1-yl]methyl]-1H-indol-1-yl]benzoic acid, 1c, could cause significant decrease on MBP in a dose dependent manner. Its maximal response lowered 53 mmHg of MBP at 5 mg/kg and 64 mmHg of MBP at 10 mg/kg after oral administration, and the significant antihypertensive effect lasted beyond 24 h, which was better than both losartan and telmisartan. A study designed to determine acute toxicity showed that 1c had low acute toxicity with no significant changes in the weight and no obvious untoward reactions. The encouraging results make 1c an effective and durable anti-hypertension drug candidate and deserve further investigation for therapeutic application.

Inhibition of Angiotensin Converting Enzyme, Angiotensin II Receptor Blocking, and Blood Pressure Lowering Bioactivity across Plant Families.

Hypertension is a major risk factor for coronary heart disease, kidney disease, and stroke. Interest in medicinal or nutraceutical plant bioactives to reduce hypertension has increased dramatically. The main biological regulation of mammalian blood pressure is via the renin-angiotensin-aldosterone system. The key enzyme is angiotensin converting enzyme (ACE) that converts angiotensin I into the powerful vasoconstrictor, angiotensin II. Angiotensin II binds to its receptors (AT1) on smooth muscle cells of the arteriole vasculature causing vasoconstriction and elevation of blood pressure. This review focuses on the in vitro and in vivo reports of plant-derived extracts that inhibit ACE activity, block angiotensin II receptor binding and demonstrate hypotensive activity in animal or human studies. We describe 74 families of plants that exhibited significant ACE inhibitory activity and 16 plant families with potential AT1 receptor blocking activity, according to in vitro studies. From 43 plant families including some of those with in vitro bioactivity, the extracts from 73 plant species lowered blood pressure in various normotensive or hypertensive in vivo models by the oral route. Of these, 19 species from 15 families lowered human BP when administered orally. Some of the active plant extracts, isolated bioactives and BP-lowering mechanisms are discussed.

A Structure-Activity Relationship Study of Imidazole-5-Carboxylic Acid Derivatives as Angiotensin II Receptor Antagonists Combining 2D and 3D QSAR Methods.

Two-dimensional (2D) and three-dimensional (3D) quantitative structure-activity relationship (QSAR) studies were performed for correlating the chemical composition of imidazole-5-carboxylic acid analogs and their angiotensin II [Formula: see text] receptor antagonist activity using partial least squares and k-nearest neighbor, respectively. For comparing the three different feature selection methods of 2D-QSAR, k-nearest neighbor models were used in conjunction with simulated annealing (SA), genetic algorithm and stepwise coupled with partial least square (PLS) showed variation in biological activity. The statistically significant best 2D-QSAR model having good predictive ability with statistical values of [Formula: see text] and [Formula: see text] was developed by SA-partial least square with the descriptors like [Formula: see text]count, 5Chain count, SdsCHE-index, and H-acceptor count, showing that increase in the values of these descriptors is beneficial to the activity. The 3D-QSAR studies were performed using the SA-PLS. A leave-one-out cross-validated correlation coefficient [Formula: see text] and predicate activity [Formula: see text] = 0.7226 were obtained. The information rendered by QSAR models may lead to a better understanding of structural requirements of substituted imidazole-5-carboxylic acid derivatives and also aid in designing novel potent antihypertensive molecules.

Nano vesicular lipid carriers of angiotensin II receptor blocker: Anti-hypertensive and skin toxicity study in focus.

OBJECTIVE: Nanoethosomal carriers of valsartan have been previously prepared, characterized and optimized. A gel formulation of valsartan vesicular lipid carriers was composed of Carbopol(®) (1% w/w), polyethylene glycol-400 (15% w/w) and triethanolamine (0.5% w/w). The influence of the valsartan nanoethosomal formulation developed on the blood pressure of experimental hypertensive rats, and its potential for skin irritation, are presented in this report. MATERIALS AND METHODS: The experimental rats were divided into three groups; the control group received no treatment (Group A). Group B was administered methyl prednisolone acetate (20 mg/kg/week) for two weeks (hypertensive control). Group C received methyl prednisolone acetate, followed by administration of the valsartan ethosomal formulation. The blood pressure of the rats was measured using a non-invasive rat blood pressure instrument based on the tail-cuff technique. The statistical analysis was performed using GraphPad InStat 3 software. RESULTS AND DISCUSSION: The treatment group showed a significant (P < 0.05) and constant fall in blood pressure, for up to 48 h. The valsartan ethosomal formulation was found to be effective, with a 34.11% reduction in blood pressure. The formulation's potential for skin irritation was assessed by the Draize irritation score test, which ruled out the possibility of any skin irritation caused by application of the formulation in rats. CONCLUSION: Our results suggest that nanoethosomes are efficient carriers for transdermal delivery of valsartan, for the management of hypertension.

Discovery of novel, potent and low-toxicity angiotensin II receptor type 1 (AT1) blockers: Design, synthesis and biological evaluation of 6-substituted aminocarbonyl benzimidazoles with a chiral center.

Novel angiotensin II receptor type 1 (AT1) blockers bearing 6-substituted carbamoyl benzimidazoles with a chiral center were designed and synthesized as the first step to develop new antihypertensive agents and understand their pharmacodynamic and pharmacokinetic properties. The newly synthesized compounds were tested for their potential ability to displace [(125)I] Sar(1) Ile(8)-Ang II, which was specifically bound to human AT1 receptor. Radioligand binding assays revealed nanomolar affinity in several compounds under study. The IC50 values of nine ligands were higher than those of Losartan. The screening of decreased blood pressure in spontaneous hypertensive rats displayed that compound 8S (IC50 = 5.0 nM) was equipotent with Losartan, whereas compounds 13R (IC50 = 7.3 nM), 14R (IC50 = 6.3 nM), and 14S (IC50 = 3.5 nM) were slightly ahead of Losartan, and the most significant activity was demonstrated by compound 8R (IC50 = 1.1 nM). Candidate 8R was identified for its excellent efficacy in antihypertension and fairly low toxicity based on plasma analyses, toxicology studies, and chronic oral tests. Finally, compound 8R exhibited strong and multiple interactions with target active sites of the theoretical AT1 receptor model in docking study.

Evaluation and Management of Proteinuria After Kidney Transplantation.

Proteinuria occurs commonly after kidney transplantation. Because there are no specific guidelines for defining and detecting proteinuria in transplant recipients, its prevalence can vary depending on the methods used. Most often, the same cutoffs for defining proteinuria in the nontransplant population are applied. There are several risk factors for proteinuria, including some transplant-specific diagnoses and immunosuppressive medications. Posttransplantation proteinuria is associated with reduced graft survival as well as an increased risk of cardiovascular events and death. Treatments to decrease proteinuria have been based on blocking the renin-angiotensin-aldosterone system with the use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. This review describes the measurement, prevalence, etiology, prognostic significance, and management of proteinuria in both adult and pediatric transplant recipients.

Synthesis and pharmacological evaluation of a novel AT1 angiotensin II receptor antagonist with anti-hypertension and anti-tumor effects.

A new compound 2-(4-((2-butyl-5-nitro-1H-benzo[d]imidazol-1-yl)methyl)-1H-indol-1-yl) benzamide (1) was designed, synthesized and evaluated as a novel AT1 receptor antagonist. Compound 1 displayed high affinity to AT1 receptor with an IC50 value of 1.65 ± 0.2 nM in radio-ligand binding assays. It had an efficient and long-lasting effect in reducing blood pressure which could last for more than 12 h at the dose of 10 mg/kg in spontaneously hypertensive rats. Acute toxicity tests suggested that compound 1 was safe with the LD50 value of 2519.81 mg/kg. Besides, in vitro and in vivo tests suggested its anti-proliferative and anti-tumor activities, respectively. So compound 1 could be considered as a novel anti-hypertension, anti-tumor candidate and deserved further investigation.

HPTLC with fluorescence densitometry for simultaneous determination of some angiotensin II receptor blockers in tablets and plasma.

A selective, accurate, precise, and highly sensitive HPTLC assay with reflectance/fluorescence densitometry was developed to separate and quantify some angiotensin II receptor blockers (ARBs), namely, losartan potassium, irbesartan, valsartan, and olmesartan medoxomil, in tablets and plasma. Separation of the target ARBs was performed on precoated silica gel HPTLC plates developed using chloroform-glacial acetic acid (7.5 + 2.5, v/v) mobile phase. The drugs were adequately resolved. After the exposure of the chromatograms to concentrated hydrochloric acid vapor for 10 min, the scanner was set in the reflectance/fluorescence mode with 255 nm excitation wavelength and >400 nm emission filter. The linear regression analysis data for the calibration curves of all studied drugs produced a good linear relationship with correlation coefficients ranging from 0.9991 to 0.9999 over the concentration range of 2-20 ng/band. LOD and LOQ values of all studied drugs ranged from 0.6 to 0.8 and from 1.7 to 2.4 ng/band, respectively. The developed method was successfully applied for analysis of the target ARBs in tablets and spiked human plasma samples with good precision and accuracy.