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The renin enzyme is considered a promising target for hypertension and renal diseases. Over the last three decades, several experimental and theoretical studies have been engaged in the discovery of potent renin inhibitors. The identified inhibitors that undergo clinical trials are still failing to meet the criteria of potency and safety. To date, there is no specific FDA-approved drug for renin inhibition. Our theoretical opinion describes that the most potent compounds identified in experimental studies but lacking safety and overdose issues could be solved by finding similar molecules that are stable, very active, and have no side effects, which will kick start the drug discovery process. Here, we utilized the most potent direct renin inhibitors reported earlier, followed further by our theoretical study reported in 2019. Ligand-based virtual screening, density functional theory, and dynamic simulation studies were employed to explore the identified compounds and co-crystallized molecule in the protein structure. From the diverse databases, we have identified several identical molecules based on their structural features, such as functional groups like hydrophobic (H), aromatic rings (R), hydrogen bond acceptor (A), and donor (D). The HHHPR five-point pharmacophore feature was identified as a template pharmacophore to search the potential compounds from the Enamine and LifeChemical databases and have a good fitness score with known renin inhibitors. Furthermore, theoretical validation was done through several studies that confirmed the activity of the identified molecules. Overall, we propose that these compounds might break the failure in adverse events and improve the potency of hypertension treatment.Communicated by Ramaswamy H. Sarma.

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Hypertension is a diverse illness interlinked with cerebral, cardiovascular (CVS) and renal abnormalities. Presently, the malady is being treated by focusing on Renin- angiotensin system (RAS), voltage-gated calcium channels, peripheral vasodilators, renal and sympathetic nervous systems. Cardiovascular and renal abnormalities are associated with the overactivation of RAS, which can be constrained by angiotensin- converting enzyme inhibitors (ACEIs), angiotensin II (Ang-II) -AT1 receptor blockers (ARBs) and renin inhibitors. The latter is a new player in the old system. The renin catalyzes the conversion of angiotensinogen to Angiotensin I (Ang-I). This can be overcome by inhibiting renin, a preliminary step, eventually hinders the occurrence of the cascade of events in the RAS. Various peptidomimetics, the first-generation renin inhibitors developed six decades ago have limited drug-like properties as they suffered from poor intestinal absorption, high liver first-pass metabolism and low oral bioavailability. The development of chemically diverse molecules from peptides to nonpeptides expanded the horizon to achieving direct renin inhibition. Aliskiren, a blockbuster drug that emerged as a clinical candidate and got approved by the US FDA in 2007 was developed by molecular modeling studies. Aliskiren indicated superior to average efficacy and with minor adverse effects relative to other RAS inhibitors. However, its therapeutic use is limited by poor oral bioavailability of less than 2% that is similar to first-generation peptidic compounds. In this review, we present the development of direct renin inhibitors (DRIs) from peptidic to nonpeptidics that lead to the birth of aliskiren, its place in the treatment of cardiovascular diseases and its limitations.

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Direct renin inhibitors (DRIs) block the activation of the alternative complement pathway in vitro and could be a treatment option for refractory hypertension in atypical hemolytic uremic syndrome (aHUS). A 20-year-old male presented with primary aHUS complicated by end-stage renal disease and refractory malignant hypertension despite being on five antihypertensive medications at maximum dose. Only a partial response was achieved with aliskiren and eculizumab, but after increasing aliskiren to a supratherapeutic dose, antihypertensive medication was reduced, platelets increased, C3 increased and epoetin alfa requirement decreased. DRI may be an adjunct treatment for malignant hypertension associated with aHUS.

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BACKGROUND: Several drugs are used for treating IgA nephropathy (IgAN). We carried out a network meta-analysis evaluating these drugs. METHODS: Electronic databases were searched for appropriate randomized clinical trials carried out in patients with IgAN. The primary outcome was proteinuria remission rates and there were several other secondary outcome measures. The risk of bias was assessed. Mixed treatment comparison estimates were modelled from direct and indirect comparison estimates. Grading of the evidence for key comparisons was carried out. RESULTS: Fifty-seven clinical trials were included in the systematic review and 51 in the metaanalysis. Polyunsaturated fatty acids, corticosteroids/angiotensin receptor blockers (ARB), ARB, angiotensin converting enzyme inhibitors (ACEI), ARB/ACEI, corticosteroids/ACEI and hypolipidemics/ ARB were observed with significantly higher rates of proteinuria remission than the standard of care. Several benefits were observed with other drugs on the secondary outcome measures. A very low grade was observed for the interventions. CONCLUSION: We observed a few interventions to perform better in the management of IgAN. The results of this study will aid in further evaluation of such drugs that may assist in saving the resources and time. However, the readers should interpret the findings with great caution as the results might change with the advent of future head-to-head clinical trials.

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See Article Cooper et al.

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Discovery of potent renin inhibitors which contain a simplified alkylamino Asp-binding group and exhibit improved selectivity for renin over Cyp3A4 is described. Structure-function results in this series are rationalized based on analysis of selected compounds bound to renin, and the contribution of each molecular feature leading to the reduced P450 inhibition is quantified.

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The renin-angiotensin-aldosterone system (RAAS) plays a key role in the pathophysiology of arterial hypertension as well as in more complex mechanisms of cardiovascular and renal diseases. RAAS-blocking agents like angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers, have long been key components in the treatment of essential hypertension, heart failure, diabetic nephropathy, and chronic kidney disease, showing benefits well beyond blood pressure reduction. Renin blockade as the first step of the RAAS cascade finally became possible in 2007 with the approval of aliskiren, the first orally active direct renin inhibitor available for clinical use and the newest antihypertensive agent on the market. In the last decade, many clinical trials and meta-analyses have been conducted concerning the efficacy and safety of aliskiren in comparison to other antihypertensive agents, as well as the efficacy and potential clinical use of various combinations. Large trials with cardiovascular and renal endpoints attempted to show potential benefits of aliskiren beyond blood pressure lowering, as well as morbidity and mortality outcomes in specific populations such as diabetics, heart failure patients, and post-myocardial infarction individuals. The purpose of this review is to present the currently available data regarding established and future potential clinical uses of aliskiren.

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In search for new drugs lowering arterial blood pressure, which could be applied in anti-hypertensive therapy, research concerning agents blocking of renin-angiotensin-aldosteron system has been conducted. Despite many years of research conducted at many research centers around the world, aliskiren is the only one renin inhibitor, which is used up to now. Four novel potential renin inhibitors, having structure based on the peptide fragment 8-13 of human angiotensinogen, a natural substrate for renin, were designed and synthesized. All these inhibitors contain unnatural moieties that are derivatives of N-methylleucyl-ß-hydroxy-γ-amino acids at the P2-P1' position: 4-[N-(N-methylleucyl)-amino]-3-hydroxy-7-(3-nitroguanidino)-heptanoic acid (AHGHA), 4-[N-(N-methylleucyl)-amino]-3-hydroxy-5-phenyl-pentanoic acid (AHPPA) or 4-[N-(N-methylleucyl)-amino]-8-benzyloxycarbonylamino-3-hydroxyoctanoic acid (AAHOA). The previously listed synthetic ß-hydroxy-γ-amino acids constitute pseudodipeptidic units that correspond to the P1-P1' position of the inhibitor molecule. An unnatural amino acid, 4-methoxyphenylalanin (Phe(4-OMe)), was introduced at the P3 position of the obtained compounds. Three of these compounds contain isoamylamide of 6-aminohexanoic acid (ε-Ahx-Iaa) at the P2'-P3' position. The proposed modifications of the selected human angiotensinogen fragment are intended to increase bioactivity, bioavailability, and stability of the inhibitor molecule in body fluids and tissues. The inhibitor Boc-Phe(4-OMe)-MeLeu-AHGHA-OEt was obtained in the form of an ethyl ester. The hydrophobicity coefficient, expressed as log P varied between 3.95 and 8.17. In vitro renin inhibitory activity of all obtained compounds was contained within the range 10(-6)-10(-9) M. The compound Boc-Phe(4-OMe)-MeLeu-AHPPA-Ahx-Iaa proved to be the most active (IC50 = 1.05 × 10(-9) M). The compounds Boc-Phe(4-OMe)-MeLeu-AHGHA-Ahx-Iaa and Boc-Phe(4-OMe)-MeLeu-AHPPA-Ahx-Iaa are resistant to chymotrypsin.

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Diabetic Kidney Disease (DKD) is the leading cause of chronic kidney disease in developed countries and its prevalence has increased dramatically in the past few decades. These patients are at an increased risk for premature death, cardiovascular disease, and other severe illnesses that result in frequent hospitalizations and increased health-care utilization. Although much progress has been made in slowing the progression of diabetic nephropathy, renal dysfunction and the development of end-stage renal disease remain major concerns in diabetes. Dysregulation of the renin-angiotensin-aldosterone system (RAAS) results in progressive renal damage. RAAS blockade is the cornerstone of treatment of DKD, with proven efficacy in many arenas. The theoretically-attractive option of combining these medications that target different points in the pathway, potentially offering a more complete RAAS blockade, has also been tested in clinical trials, but long-term outcomes were disappointing. This review examines the "state of play" for RAAS blockade in DKD, dual blockade of various combinations, and a perspective on its benefits and potential risks.

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To exploit the S3' subsite of renin active site for renin inhibitor design, 42 aliskiren derivatives with modified P2' portion were designed, synthesized and biologically evaluated. Some highly potent renin inhibitors (IC50 < 3 nM) were identified, among which compounds 38 (IC50 = 0.9 nM) and 39 (IC50 = 0.7 nM) were over 2.5-fold more potent than aliskiren (IC50 = 2.3 nM). SAR analysis indicated that incorporation of polar hydrophilic moieties into the P2' portion of renin inhibitors generally enhanced the potency. Consistently with this, molecular modeling study revealed that the triazole part of 39 could provide additional interactions to the S3' subsite of renin active site. Moreover, in vivo evaluation in the double transgenic mouse hypertension model demonstrated that 39 produced greater reduction of the mean arterial blood pressure than ariskiren at the doses of 17.0 and 34.0 µmol/kg, respectively. Taken together, the S3' subsite of renin active site merits further consideration for renin inhibitor design.

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The development of renin inhibitors with favorable oral pharmacokinetic profiles has been a longstanding challenge for the pharmaceutical industry. As part of our work to identify inhibitors of BACE1, we have previously developed iminopyrimidinones as a novel pharmacophore for aspartyl protease inhibition. In this letter we describe how we modified substitution around this pharmacophore to develop a potent, selective and orally active renin inhibitor.

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HYPOTHESIS/INTRODUCTION: The aim of this study was to assess the antihypertensive efficacy and safety of aliskiren versus ramipril or losartan in hypertensive patients with type 2 diabetes mellitus, microalbuminuria and uncontrolled hypertension, despite the use of optimal conventional antihypertensive therapy. MATERIALS AND METHODS: In this open-label active comparator study, 126 patients were randomly assigned to receive 24 weeks of additional therapy with aliskiren (Group A) or either losartan or ramipril (Group B), according to whether a patient was already treated with an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker, respectively. RESULTS: After 24 weeks, both treatment groups experienced a significant reduction of systolic blood pressure (-11.37% and -8.47%, respectively; both p <0.001 vs. baseline) and diastolic blood pressure levels (-10.67% and -9.28%, respectively; both p <0.001 vs. baseline), with a greater reduction of mean systolic values in Group A compared with Group B (p <0.001). Furthermore, after six months microalbuminuria was significantly decreased in both treatment groups (-67.62% and -49.1%, respectively; both p <0.001), with a reduction rate in Group A significantly higher than in Group B (p<0.001). CONCLUSIONS: The addition of aliskiren to optimal conventional therapy provided a higher reduction of blood pressure and urinary albumin excretion when compared with the addition of losartan or ramipril.

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AIM: Non-alcoholic steatohepatitis (NASH) is a manifestation of metabolic syndrome in the liver that is characterized by hepatic fat accumulation, inflammation and varying degrees of fibrosis. The renin-angiotensin system (RAS) appears to play important roles in NASH. Direct renin inhibitors (DRI) reduce plasma renin activity (PRA) through interaction with the active site of the enzyme and reduce the formation of angiotensin-II (AT-II). Therefore, the DRI aliskiren may further suppress the RAS. This study examined the effects of aliskiren on NASH in fatty liver Shionogi (FLS)-ob/ob male mice that are the closest animal model of metabolic syndrome-related NASH in humans. METHODS: Aliskiren (100 mg/kg per day, aliskiren group) or a placebo (control group) was p.o. administrated to eight FLS-ob/ob mice each for 16 weeks and factors including steatosis, fibrosis, inflammation and oxidative stress were compared between the two groups. RESULTS: Amounts of hepatic fibrosis were significantly lower in the aliskiren group than in the control group. Areas of α-smooth muscle actin positivity, the numbers of F4/80 positive, 8-hydroxy-2-deoxyguanosine positive cells and immunohistochemical staining of 4-hydroxynonenal were also significantly decreased in the aliskiren group. Levels of RNA expression for transforming growth factor-ß1, connective tissue growth factor and monocyte chemoattractant protein-1 were significantly lower in the aliskiren group. CONCLUSION: Aliskiren attenuated the progression of hepatic fibrosis by inhibiting the activation of hepatic stellate and Kupffer cells and by reducing oxidative stress.

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OBJECTIVE: Angiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme (ACE) inhibitors are known to reduce proteinuria and have been the first-line agents in the management of diabetic nephropathy for the past 20 years. This review covers recent studies that compare the benefit of additional blockage of the renin-angiotensin-aldosterone system through combination therapy with an ACE inhibitor and ARB, or a direct renin inhibitor (DRI), to monotherapy. DESIGN: Primary and review articles that addressed the pathophysiology, diagnosis, and therapeutic options for attenuating the progression of diabetic nephropathy were retrieved through a MEDLINE search (January 1990 to December 2012) and the bibliographies of identified articles were reviewed. English language sources were searched using the following search terms: diabetes mellitus, nephropathy, proteinuria, ACE inhibitors, ARBs, and DRIs. SETTING: Randomized, placebo-controlled, short- and long-term studies published in peer-reviewed journals that were determined to be methodologically sound, with appropriate statistical analysis of the results, were selected for inclusion in this review. PARTICIPANTS: Adult (≥18 years) patients with diabetic nephropathy. MEASUREMENTS: Serum creatinine level was used to estimate glomerular filtration rate (GFR). GFR was calculated using the four-variable Modification of Diet in Renal Disease formula. The urine albumin-to-creatinine ratio was measured at baseline and at the conclusion of each study. A value between 3.4 mg/mmol and below 33.9 mg/mmol was defined as microalbuminuria. A value of 33.9 mg/mmol or more (approximately 300 mg/g creatinine) was defined as macroalbuminuria. RESULTS: ACE inhibitors and ARBs are now the mainstay of treatment for diabetic nephropathy. However, combination therapy with an ACE inhibitor and an ARB, or DRI, has not been found to be more effective than monotherapy with an ACE inhibitor or ARB, and may increase the risk of hyperkalemia or acute kidney injury. CONCLUSION: Both ACE inhibitors and ARBs remain the first-line agents in attenuating the progression of diabetic nephropathy; however, recent studies suggest that combining an ACE inhibitor with an ARB, or combining a DRI with an ACE inhibitor or ARB, may increase adverse events without clinical benefits to offset them.

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Renin inhibitors are antihypertensive drugs that block the first step in the renin-angiotensin system. Their mechanism of action differs from that of the angiotensin-converting enzyme inhibitors and angiotensin-receptor antagonists, but like these drugs, renin inhibitors interrupt the negative feedback effects of angiotensin II on renin secretion. The renin-angiotensin-aldosterone system (RAAS) has long been recognized to play a significant role in hypertension pathophysiology. Certain agents that modify the RAAS can control blood pressure and improve cardiovascular outcomes. Optimization of this compound by Novartis led to the development of aliskiren - the only direct renin inhibitor which is clinically used as an antihypertensive drug. Aliskiren is the first of a new class of antihypertensive agents. Aliskiren is a new renin inhibitor of a novel structural class that has recently been shown to be efficacious in hypertensive patients after once-daily oral dosing. In short-term studies, it was effective in lowering blood pressure either alone or in combination with valsartan and hydrochlorothiazide, and had a low incidence of serious adverse effects. It was approved by the Food and Drug Administration in 2007 for the use as a monotherapy or in combination with other antihypertensives. Greater reductions in blood pressure have been achieved when aliskiren was used in combination with hydrochlorothiazide or an angiotensin-receptor blocker. The most common adverse effects reported in clinical trials were headache, fatigue, dizziness, diarrhea, and nasopharyngitis. Aliskiren has not been studied in patients with moderate renal dysfunction; as an RAAS-acting drug, it should be prescribed for such patients only with caution.

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Aliskiren, the first orally active direct renin inhibitor, is an effective antihypertensive drug with distinctive characteristics, including good blockade of the renin-angiotensin system, a prolonged duration of action, pharmacologic effects that persist after drug discontinuation, and favorable tolerability comparable with placebo. The blood pressure-lowering effect of aliskiren monotherapy is similar, if not superior, to that of other first-line antihypertensive agents, and is greatly enhanced when aliskiren is combined with various other antihypertensive medications, without any adverse drug interactions. Aliskiren is also an effective and well tolerated therapy in special populations, including diabetic, obese, and elderly hypertensives. Beyond its blood pressure-lowering efficacy, results from experimental and clinical trials suggest that aliskiren has positive effects on markers of cardiovascular and renal damage. The ASPIRE (Aliskiren Study in Post-MI patients to Reduce rEmodelling) HIGHER clinical trials program is further assessing whether the promising pharmacologic properties of aliskiren translate into reduced risk of adverse cardiovascular and renal outcomes.

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The renin-angiotensin-aldosterone system (RAAS) is a key mediator of blood pressure (BP) and volume regulation in both normotensive and hypertensive persons. Stimulation of RAAS also contributes to hypertension-related target organ damage. The renin-angiotensinogen reaction is the first and rate-limiting step in the generation of angiotensin II (Ang II) and has been a target of antihypertensive drug development for decades. Aliskiren is the first in a new class of orally effective direct renin inhibitors (DRIs) and is approved for the treatment of hypertension in humans. It effectively reduces BP in the general population of hypertensive patients and has a tolerability and safety profile similar to placebo. Aliskiren has favorable effects on vascular inflammation and remodeling, on neurohumoral mediators of various forms of cardiovascular disease, including heart failure, and on proteinuria in diabetic patients. Additional outcome trials are needed to establish the role of this novel class of antihypertensive medication in preventing cardiovascular disease morbidity and mortality.

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Hypertension is a major risk factor for the development of cardiovascular and renal disease. The incidence of hypertension is increasing globally and the rate of blood pressure control remains inadequate. Renin-angiotensin-aldosterone system (RAAS) plays a crucial role in volume regulation and maintenance of blood pressure. Pathological activation of RAAS results in chronic hypertension and consequent end organ damage. Most patients with hypertension require combination therapy using agents with complimentary mechanisms of action. Hydrochlorothiazide (HCTZ) together with an agent blocking the RAAS such as an angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) are widely used effective anti-hypertensive therapy. Aliskiren is an orally effective direct renin inhibitor that blocks the generation of angiotensin I from angiotensinogen, the rate limiting step of RAAS activation. Studies have shown equivalent antihypertensive efficacy of aliskiren when compared to existing medications such as HCTZ, ACE inhibitors and ARBs. Aliskiren has also been tested in combination therapies. The current review aims to look at the efficacy of aliskiren therapy in hypertension and the evidence for using aliskiren in combination with HCTZ.

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