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The renin protein is an upstream enzymatic regulator of the renin-aldosterone-angiotensin system (RAAS) essential for the maintenance of blood pressure. The angiotensin-converting enzyme-2 (ACE2) is a major component of the RAAS and a cell surface receptor exploited by the SARS-CoV-2 virus to enter host cells. A recent molecular modeling study has revealed that the direct renin peptide inhibitor remikiren can bind to the catalytic site of SARS-CoV-2 main protease (M pro ). By analogy, we postulated that the non-peptidic drug aliskiren, a more potent renin inhibitor than remikiren and a drug routinely used to treat hypertension, may also be able to interact with M pro . An in silico comparison of the binding of the two compounds to M pro indicates that aliskiren (ΔE = -75.9 kcal/mol) can form stable complexes with the main viral protease, binding to the active site, as remikiren (ΔE = -83.2 kcal/mol). The comparison with a panoply of 30 references compounds (mainly antiviral drugs) indicated that remikiren is a potent M pro binder comparable to drugs like glecaprevir and pibrentasvir (ΔE = -96.5 kcal/mol). The energy of interaction (ΔE) of aliskiren with M pro is about 10% lower than with remikiren, comparable to that calculated with drugs like velpatasvir and sofosbuvir. A model is proposed to define the drug binding site, with the best binders (including remikiren) penetrating deeply into the site, whereas the less potent binders (including aliskiren) interact more superficially with the protein.Communicated by Ramaswamy H. Sarma.

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

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-β-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 β-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., (Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.)

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., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

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., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

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.

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.

BACKGROUND The rehospitalization rate in a hypertensive emergency is high, indicating the necessity for optimizing its long-term management. The role of the renin–angiotensin system (RAS) blockade in this disorder remains uncertain. METHODS We conducted a retrospective analysis involving 20 admitted patients who received aliskiren, a direct renin inhibitor (DRI), for the management of hypertensive emergency associated with elevated plasma renin activity (PRA). We analyzed the changes in blood pressure (BP), kidney function, and RAS activity in the subacute and chronic phases. RESULTS The use of DRI was associated with a marked reduction in PRA (median, from 25.0 to 1.2 ng/ml/h) and serum aldosterone levels (from 404 to 130 pg/ml) during the index admission. BP also decreased from 226/143 to 142/80 mm Hg. A comparison of clinical characteristics according to the renal function indicated that dialysis-dependent patients had higher aldosterone levels than non-dialysis-dependent patients at admission, despite comparable BP levels. After a median follow-up of 567 days in non-dialysis-dependent patients with DRI, eGFR levels were significantly increased from 14.3 to 23.1 ml/min/1.73 m2. PRA levels were consistently suppressed at 0.8 ng/ml/h. We found a significant correlation between the degree of PRA suppression and changes in eGFR (r  = –0.58), indicating that the effective blockade of RAS is associated with the preservation of eGFR in the study subjects. CONCLUSIONS DRI can successfully suppress PRA in patients with high-renin hypertensive emergency in both subacute and chronic phases. An efficient RAS blockade is associated with preserved renal function in these patients. [ABSTRACT FROM AUTHOR]

Renin inhibitors derived from natural ingredients often belong to the saponin or polyphenol chemical class. Pegagan (Centella asiatica) is a natural plant in Indonesia that contains saponins and polyphenols. The active compounds of Pegagan include asiaticoside, madasiatic acid, madecassoside, madecassic acid, and asiatic acid. This study investigates the possible renin-inhibitory properties of phytochemicals from Centella asiatica using in-silico molecular docking. Using AutoDock v4.2.6, up to five C. asiatica compounds were docked with 2V0Z Renin with Inhibitor 10 (Aliskiren) in human subjects (Homo sapiens 6LU7). These compounds included asiaticoside, madasiatic acid, madecassoside, madecassid acid, and asiatic acid. SwissADME was used to evaluate these drugs' pharmacokinetic characteristics. The molecular docking results of 5 test ligands obtained affinity energy values from -8.7 kcal/mol to -10.4 kcal/mol. In contrast, the affinity energy value for the comparison ligand (aliskiren) is -9.0 kcal/mol. Madecasosside has an affinity energy value of -10.4 kcal/mol, asiaticoside of -9.6 kcal/mol and asiatic acid of -9.2 kcal/mol. Based on this energy affinity value, the active compound C. asiatica has the potential as a renin inhibitor. Pharmacokinetic analysis revealed that asiatic acid, madecassic acid, madasiatic acid, and asiatic acid have good pharmacokinetic properties. It may be concluded based on in silico molecular docking and pharmacokinetics investigation that the molecule most strongly suggested for additional in vitro renin inhibitor research was asiatic acid. Keywords: Renin Inhibitor, Centella asiatica, Molecular Docking. [ABSTRACT FROM AUTHOR]

This article is a response to a letter from A.H. Jan Danser and Ingrid M. Garrelds regarding the clinical impact of sample storage at -20 °C on renin reference intervals and aldosterone-renin ratio calculations. The authors of the response paper argue that cryoactivation of prorenin is a preanalytical risk for renin measurements in plasma samples stored at -20 °C. They cite experiments that show highly variable increases in renin concentration when samples are frozen at -20 °C, but no cryoactivation when samples are snap-frozen or defrosted at ambient temperature. Based on this evidence, the authors advise laboratories to store plasma samples for renin analyses in a -70 °C freezer or snap-freeze samples and store them in a -20 °C freezer. [Extracted from the article]

The article discusses the phenomenon of cryoactivation, which refers to a cold-induced change in prorenin, the inactive precursor of renin. The authors explain that storing plasma samples at low temperatures for a long time can lead to the inactivation of serine protease inhibitors, resulting in the generation of kallikrein, which can cleave the prosegment of prorenin. The authors argue that storing samples at -20 °C is sufficient and that there is no advantage to storing them at -70 °C. They also mention that renin inhibitors can bind to the active site of prorenin, leading to overestimation of renin levels in certain assays. [Extracted from the article]

Introduction: Renin-angiotensin system inhibitors have been reported to exert protective effects against organ damage and failure; however, the impact of the direct renin inhibitor as monotherapy has not been assessed. Here, we investigated the effects of 24-week monotherapy with aliskiren compared to amlodipine in hypertensive patients with type 2 diabetes or obesity. Methods: In this randomized intervention study, 62 adult hypertensive patients with visceral obesity (defined as a body mass index [BMI] greater than 25 kg/m2 and a visceral adipose tissue area [VFA] greater than 100 cm2) or type 2 diabetes mellitus (age 57 ± 13, 65% men, BMI 28.8 ± 4.8 kg/m2, VFA 134.8 ± 47.0 cm2, blood pressure 141 ± 16/86 ± 13 mm Hg) were randomized to receive 24-week treatment with aliskiren (max. 300 mg) or amlodipine (max. 10 mg). The primary outcome was the change in VFA at 24 weeks post-treatment. Results: Change in VFA did not differ significantly from baseline in either group. Systolic blood pressure significantly decreased at 12 weeks (−10 mm Hg, p = 0.001) and 24 weeks (−10 mm Hg, p = 0.001) in the amlodipine group and at 24 weeks (−11 mm Hg, p = 0.001) in the aliskiren group. Diastolic blood pressure significantly decreased at 24 weeks (−6 mm Hg, p = 0.009) only in the amlodipine group. Although the estimated glomerular filtration rates did not significantly change in either group, the logarithm of urinary albumin excretion significantly decreased at 24 weeks only in the aliskiren group (−0.60, p < 0.001). The 24-week changes in the urinary albumin excretion significantly correlated with the changes in the plasma renin activity in the aliskiren group (r = 0.51, p = 0.008). Conclusion: Aliskiren monotherapy did not show any superiority to amlodipine monotherapy on VFA, estimated glomerular filtration rates, or urinary albumin excretion in obese or type 2 diabetic hypertensive patients. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic has urged for the repurposing of existing drugs for rapid management and treatment. Renin inhibitors down regulation of ACE2, which is an essential receptor for SARS-CoV-2 infection that is responsible for COVID-19, in addition to their ability to act as protease inhibitors were encouraging aspects for their investigation as possible inhibitors of main protease of SARS-CoV-2 via computational studies. A Pharmacophore model was generated using the newly released SARS-COV-2 main protease inhibitors. Virtual screening was performed on renin inhibitors, and Drug likeness filter identified remikiren and 0IU as hits. Molecular docking for both compounds showed that the orally active renin inhibitor remikiren (Ro 42–5892) of Hoffmann–La Roche exhibited good molecular interaction with Cys145 and His41 in the catalytic site of SARS-CoV-2 main protease. Molecular dynamics simulation suggested that the drug is stable in the active site of the enzyme. Image 1 • For rapid management of COVID-19, drug repurposing was widely carried out. • Renin inhibitors downregulate ACE2, decreasing the risk of SARS-COV-2 infection. • SARS-COV-2 main protease is a potential target for renin inhibitors. • Pharmacophore model was generated and virtually screened on renin inhibitors. • Remikiren was a hit, furtherly studied through molecular docking and dynamics. [ABSTRACT FROM AUTHOR]

Seven novel potential renin inhibitors, having a structure based on the peptide fragment 8-13 of human angiotensinogen - a natural substrate for renin, have been designed and synthesized. All peptides were obtained by the carbodiimide method in solution and purified by chromatography on the SiO2 column. In P1-P3' positions, they contain esters or N-alkyl amides of modified (3S, 4S)-4-amino-3-hydroxyacids. The achieved inhibitory activity IC50 was of 10-6-10-7M Inhibitory activity of the compounds was measured in vitro by high-performance liquid chromatography (HPLC) determination of lowering the concentration of substrate in the presence of renin and the potential rennin inhibitor. Their resistance to enzymatic degradation was assayed by the determination of stability against chymotrypsin activity. Their hydrophobicity evaluated as a Log P-value was calculated by a computer method. The theoretical binding affinity of thus obtained inhibitors was elaborated based on docking to the S3-S3' pocket of the renin active site. [ABSTRACT FROM AUTHOR]

We previously identified 2- tert -butyl-4-[(3-methoxypropyl)amino]- N -(2-methylpropyl)- N -[(3 S ,5 R )-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]pyrimidine-5-carboxamide 3 as a potent renin inhibitor. Since 3 showed unacceptably low bioavailability (BA) in rats, structural modification, using SBDD and focused on physicochemical properties was conducted to improve its PK profile while maintaining renin inhibitory activity. Conversion of the amino group attached at the 4-position of pyrimidine to methylene group improved PK profile and decreased renin inhibitory activity. New central cores with carbon side chains were explored to improve potency. We had designed a series of 5-membered azoles and fused heterocycles that interacted with the lipophilic S3 pocket. In the course of modification, renin inhibitory activity was enhanced by the formation of an additional hydrogen bonding with the hydroxyl group of Thr77. Consequently, a series of novel benzimidazole derivatives were discovered as potent and orally bioavailable renin inhibitors. Among those, compound 13 exhibited more than five-fold of plasma renin inhibition than aliskiren in cynomolgus monkeys at dose ratio. [ABSTRACT FROM AUTHOR]

Renin is an aspartyl protease of the renin–angiotensin system (RAS) and the first enzyme of the biochemical pathway for the generation of angiotensin II – a potent vasoconstrictor involved in the maintenance of cardiovascular homeostasis and the regulation of blood pressure. High enzymatic specificity of renin and its involvement in the catalysis of the rate-limiting step of the RAS hormone system qualify it as a good target for inhibition of hypertension and other associated diseases. Ligand-based pharmacophore model (Hypo1) was generated from a training set of 24 compounds with renin inhibitory activity. The best hypothesis consisted of one Hydrogen Bond Acceptor (HBA), three Hydrophobic Aliphatic (HY-Al) and one Ring Aromatic (AR) features. This well-validated pharmacophore hypothesis (correlation coefficient 0.95) was further utilized as a 3D query to screen database compounds, which included structures from two natural product repositories. These screened compounds were further analyzed for drug-likeness and ADMET studies. The compounds which satisfied the qualifying criteria were then subjected to molecular docking and Density Functional Theory (DFT) analysis in order to discern their atomic level interactions at the active site of the 3D structure of rennin. The pharmacophore-based modelling that has been used to generate the novel findings of the present study would be an avant-garde approach towards the development of potent inhibitors of renin. [ABSTRACT FROM AUTHOR]

We have applied simulated annealing of chemical potential (SACP) to a diverse set of ∼150 very small molecules to provide insights into new interactions in the binding pocket of human renin, a historically difficult target for which to find low molecular weight (MW) inhibitors with good bioavailability. In one of its many uses in drug discovery, SACP provides an efficient, thermodynamically principled method of ranking chemotype replacements for scaffold hopping and manipulating physicochemical characteristics for drug development. We introduce the use of Constrained Fragment Analysis (CFA) to construct and analyze ligands composed of linking those fragments with predicted high affinity. This technique addresses the issue of effectively linking fragments together and provides a predictive mechanism to rank order prospective inhibitors for synthesis. The application of these techniques to the identification of novel inhibitors of human renin is described. Synthesis of a limited set of designed compounds provided potent, low MW analogs (IC 50 s < 100 nM) with good oral bioavailability (F > 20–58%). [ABSTRACT FROM AUTHOR]

It is well known that endogenous bioactive proteins and peptides play a substantial role in the body's first line of immunological defence, immune-regulation and normal body functioning. Further, the peptides derived from the luminal digestion of proteins are also important for body function. For example, within the peptide database BIOPEP ( http://www.uwm.edu.pl/biochemia/index.php/en/biopep ) 12 endogenous antimicrobial and 64 angiotensin-I-converting enzyme (ACE-I) inhibitory peptides derived from human milk and plasma proteins are listed. The antimicrobial peptide database ( http://aps.unmc.edu/AP/main.php ) lists over 111 human host-defence peptides. Several endogenous proteins are secreted in the gut and are subject to the same gastrointestinal digestion processes as food proteins derived from the diet. The human gut endogenous proteins (GEP) include mucins, serum albumin, digestive enzymes, hormones, and proteins from sloughed off epithelial cells and gut microbiota, and numerous other secreted proteins. To date, much work has been carried out regarding the health altering effects of food-derived bioactive peptides but little attention has been paid to the possibility that GEP may also be a source of bioactive peptides. In this review, we discuss the potential of GEP to constitute a gut cryptome from which bioactive peptides such as ACE-I inhibitory, renin inhibitory and antioxidant peptides may be derived. [ABSTRACT FROM AUTHOR]

Hypertension is the main cause of human death and the Renin- Angiotensin- Aldosterone System (RAAS) has a key role in the control of human blood pressure. In this research a multi-step virtual screening strategy was applied in order to find new potential renin inhibitors. The crystal structure of renin-aliskiren complex was explored and receptor-ligand pharmacophore model was developed and validated using pharmit. ZINC database was screened by pharmacophore model and Lipinski's rule of five. Thereafter, the retrieved hits were docked in the active site of renin by using Vina. ADME parameters and toxicity of the filtered compounds were approximated using in silico methods and the selected compounds were subjected to high performance docking in order to improve the accuracy of screening. The non-bond interactions of the hit molecules with renin were explored and the compounds with the highest affinity and appropriate interactions were selected. In the last step, molecular dynamic simulation studies were performed on the complex of renin with aliskiren and three top-ranked structures including ZINC6085004, ZINC426421106, and ZINC5481346. RMSD, RMSF, Rg and number of hydrogen bonds were calculated. The binding free energy was calculated using the MM/PBSA method. The result of MD simulation indicated the stable binding of ZINC426421106 and ZINC5481346 with the active site of renin. According to this in-silico study these two compounds are drug-like, nontoxic, and have a high potential for inhibiting renin and could serve as appropriate lead molecules for the development of renin inhibitors as antihypertensive agents. Representation of the overall virtual screening process. [Display omitted] • A structure-based pharmacophore model was developed and validated for the renin-aliskiren complex. • ZINC database was screened by the pharmacophore model. • Molecular dynamic simulation studies were performed on the complex of renin with top-ranked structures. • The binding free energy was calculated using the MM/PBSA method. • Two molecules had a high potential for inhibition of human renin. [ABSTRACT FROM AUTHOR]

This article provides a review of the role of aliskiren, a direct renin inhibitor, in pediatric hypertension and kidney diseases. Among the many mechanisms involved in regulating blood pressure, the renin-angiotensin-aldosterone system (RAAS) plays a major role. Additionally, the RAAS has been identified as a contributing factor to cardiovascular and renal diseases for more than three decades. The potential benefits of inhibiting the RAAS by aliskiren alone or in combination with other RAAS blockers (ACEIs, ARBs) seem to be theoretically promising. However, caution should be exercised in treating children, especially in those with significant chronic kidney disease until there is more evidence regarding the safety and efficacy of this new drug in the pediatric population from ongoing clinical trials. [ABSTRACT FROM AUTHOR]

Abstract: The recently introduced field-based QSAR was employed to develop robust quantitative 3D QSAR models to comprehend the activity of several structurally diverse classes of small molecule renin inhibitors reported in literature. A reasonable predictive model with an r 2 (pred) of ∼0.67 and rmse of 0.79 was achieved for an external validation set of ∼150 compounds centered on the model developed using ∼450 training set compounds. Based on the developed 3D QSAR models and additional insights gained from reported X-ray structures, opportunity for activity improvements in the [aza]indole scaffold was explored using a carefully designed virtual library of ∼2300 compounds. The potential for success of such combined structure-guided and ligand-based approach was justified when the resulting prediction was compared against a representative with supporting experimental results. [Copyright &y& Elsevier]

Abstract: A new integrated computational workflow that couples the strength of the molecular overlay methods to achieve rapid and automated alignments along with 3D-QSAR techniques like CoMFA® and CoMSIA for quantitative binding affinity prediction is presented. The results obtained from such techniques are compared with rule-based Topomer CoMFA® method, where possible. The developed 3D-QSAR models were prospectively used to predict the affinities of new compounds designed through R-group deconvolution starting from the core chemical scaffold and subsequent virtual combinatorial library enumeration. The general applicability of the seamless in silico modeling workflow is demonstrated using several datasets reported for small molecule inhibitors of renin. [Copyright &y& Elsevier]

Abstract: Structure-based design led to the discovery of a novel class of renin inhibitors in which an unprecedented phenyl ring filling the S1 site is attached to the phenyl ring filling the S3 pocket. Optimization for several parameters including potency in the presence of human plasma, selectivity against CYP3A4 inhibition and improved rat oral bioavailability led to the identification of 8d which demonstrated antihypertensive efficacy in a transgenic rat model of human hypertension. [Copyright &y& Elsevier]

Abstract: Eighteen octane-carboxamide based renin inhibitors with extended segments for mimicking P3′ unit of angiotensinogen have been synthesized. The biological evaluation identified novel renin inhibitors with more potent activity than aliskiren. Molecular docking studies showed that the extended amide-tails matched the P3′ position of angiotensinogen and exerted interactions with the S3′ site of renin. An unexpected π–π stacking interaction was observed during docking study for compound 9r, which could be a reasonable explanation for the outstanding potency of this compound. Further study is in progress to reveal a feasibility for developing novel renin inhibitors based on the possible non-classical interactions between the ligands and the new subsite of renin. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

Renin-angiotensin-aldosterone systems play a major role in the regulation of human homeostasis mechanism, which are also involved in the development of hypertension and end-organ damage through activation of angiotensin II. Inhibitors of the renin-angiotensin-aldosterone system may reduce the development of end-organ damage to a greater extent than other antihypertensive agents. Aliskiren is the first member of the new class of orally active direct renin inhibitors recently approved by the US Food and Drug Administration for the treatment of hypertension. Aliskiren directly inhibiting the renin and reducing the formation of angiotensin II, which is the most effective mediator involved in the pathogenesis of cardiovascular diseases. The present review mainly focuses on the pharmacodynamics and pharmacokinetics and clinical aspects of aliskiren. In this respect, the review will improve the basic idea to understand the pharmacology of aliskiren, which is useful for the further research in cardiovascular disease. [ABSTRACT FROM AUTHOR]

Abstract: For the first time, a set of renin inhibitors were subjected to the 3D QSAR/CoMFA and CoMSIA studies. The utility of renin inhibitors in the treatment of cardiovascular diseases has not been fully explored yet. At the moment, aliskiren is the first and only existing renin inhibitor in the drug market. The performed 3D QSAR/CoMFA and CoMSIA in combination with docking studies included aliskiren and 37 derivatives possessing a wide variety of bioactivity. The obtained results may aid in the design of novel bioactive renin inhibitors. [Copyright &y& Elsevier]

We conducted a systematic review and meta-analysis of double-blind randomized controlled trials to quantify the dose-related systolic (SBP) and diastolic blood pressure (DBP) lowering efficacy of renin inhibitors vs placebo in the treatment of adults with primary hypertension. Databases searched were Medline (1966–March 2008), EMBASE (1988–March 2008) and Cochrane Central Register of Controlled Trials (CENTRAL). Six trials in 3694 patients met the inclusion criteria. All examined aliskiren, the only renin inhibitor licensed for marketing in Canada and the United States. Aliskiren caused a dose-related SBP/DBP lowering effect compared to placebo: weighted mean difference with 95% CI: aliskiren 75 mg, −2.9 (−4.6, −1.3)/−2.3 (−3.3, −1.3) mm Hg; aliskiren 150 mg, −5.5 (−6.5, −4.4)/−3.0 (−3.7, −2.3) mm Hg; aliskiren 300 mg, −8.7 (−9.7,−7.6)/−5.0 (−5.6, −4.3) and aliskiren 600 mg, −11.4 (−13.5, −9.2)/−6.6 (−7.9, −5.2) mm Hg. Aliskiren 300 mg significantly lowered both SBP −3.0 (−4.0, −2.0) and DBP −1.7 (−2.3, −1.0) as compared to aliskiren150 mg. Aliskiren has no effect on blood pressure variability. No data were available to assess the effect of aliskiren on heart rate or pulse pressure. This review found weak evidence that during 4- to 8-week use, aliskiren did not increase withdrawals due to adverse effects as compared to placebo. We concluded that aliskiren has a dose-related blood pressure lowering effect better than placebo and magnitude of effect is similar to that determined for angiotensin-converting enzyme inhibitors and angiotensin receptor blockers.Journal of Human Hypertension (2009) 23, 495–502; doi:10.1038/jhh.2008.162; published online 22 January 2009 [ABSTRACT FROM AUTHOR]

Aliskiren is the first member of the new class of orally active direct renin inhibitors to receive approval from the United States Food and Drug Administration for the treatment of hypertension. In patients with hypertension, aliskiren can be used either as monotherapy or in combination with other antihypertensive agents. By inhibiting renin, aliskiren blocks the conversion of angiotensinogen to angiotensin I, which subsequently results in a reduction in angiotensin II concentrations. Unlike the angiotensin-converting enzyme inhibitors and the angiotensin II receptor blockers (ARBs), which reactively stimulate an increase in plasma renin activity, aliskiren suppresses the effects of renin and leads to a reduction in plasma renin activity. In clinical trials involving patients with mild-to-moderate hypertension, aliskiren provided antihypertensive efficacy that was comparable to that of an ARB. Combination therapy with aliskiren and an ARB may provide additional blood pressure-lowering effects compared with the respective monotherapies with each of the agents. The results from surrogate outcome studies have also alluded to the potential for aliskiren to prevent target organ damage. Because aliskiren does not significantly affect the cytochrome P450 system, it has been associated with few drug interactions. In clinical studies, aliskiren was well tolerated, and its adverse-effect profile was similar to that of placebo. Fatigue, headache, dizziness, diarrhea, nasopharyngitis, and back pain were the most commonly reported adverse events. Overall, aliskiren appears to be a reasonable treatment option for patients with mild-to-moderate hypertension who are intolerant of first-line antihypertensive therapies. Aliskiren may also be a promising renoprotective strategy in patients with concomitant hypertension and diabetes mellitus. Its potential as a first-line antihypertensive agent will have to be further examined once studies evaluating its effects on long-term clinical outcomes are completed. [ABSTRACT FROM AUTHOR]

Despite improvements in its detection and treatment, hypertension remains a significant public health problem worldwide. In recent years, many international hypertension societies and organisations have set increasingly rigorous blood pressure (BP) targets, with the aim of reducing cardiovascular complications, and this has in turn necessitated the use of more antihypertensive medications to reach these targets in individual patients. There is therefore an ongoing need to develop antihypertensive drugs with new mechanisms of action. Renin inhibitors represent a novel class of compounds which offer considerable promise as BP-lowering agents. Here, we review the rationale for renin inhibition as a therapeutic target and examine the preclinical and clinical evidence for the antihypertensive effectiveness of the renin inhibitors. [ABSTRACT FROM AUTHOR]

The expression and function in growth and apoptosis of the renin-angiotensin system (RAS) was evaluated in human glioblastoma. Renin and angiotensinogen (AGT) mRNAs and proteins were found by in situ hybridisation and immunohistochemistry in glioblastoma cells. Angiotensinogen was present in glioblastoma cystic fluids. Thus, human glioblastoma cells produce renin and AGT and secrete AGT. Human glioblastoma and glioblastoma cells expressed renin, AGT, renin receptor, AT2 and/or AT1 mRNAs and proteins determined by RT-PCR and/or Western blotting, respectively. The function of the RAS in glioblastoma was studied using human glioblastoma cells in culture. Angiotensinogen, des(Ang I)AGT, tetradecapaptide renin substrate (AGT1-14), Ang I, Ang II or Ang III, added to glioblastoma cells in culture, did not modulate their proliferation, survival or death. Angiotensin-converting enzyme inhibitors did not diminish glioblastoma cell proliferation. However, the addition of selective synthetic renin inhibitors to glioblastoma cells decreased DNA synthesis and viable tumour cell number, and induced apoptosis. This effect was not counterbalanced by concomitant addition of Ang II. In conclusion, the complete RAS is expressed by human glioblastomas and glioblastoma cells in culture. Inhibition of renin in glioblastoma cells may be a potential approach to control glioblastoma cell proliferation and survival, and glioblastoma progression in combination therapy.British Journal of Cancer (2004) 90, 1059-1068. doi:10.1038/sj.bjc.6601646 www.bjcancer.com [ABSTRACT FROM AUTHOR]

Renin catalyzes the rate‐determining step in the renin–angiotensin–aldosterone system that regulates mammalian blood pressure by converting angiotensinogen to angiotensin I (Ang I). Excessive plasma levels of Ang I is a causative factor in hypertension development. Therefore, inhibition of renin activity can lower blood pressure and provide relief from clinical symptoms associated with hypertension. Synthetic compounds are currently the most used group of renin inhibitors; however, only aliskiren is approved as a drug for hypertension treatment. But some negative side effects are associated with aliskiren therapy, which have necessitated the search for alternative natural compounds such as food protein‐derived renin‐inhibitory peptides with blood pressure‐reducing effects. This paper is a concise review of the currently known sources and methods of production of renin‐inhibitory peptides including their potential in vitro and in vivo extent of renin inhibition. Practical applications: Hypertension is a major human chronic disease that leads to severe cardiovascular impairment and ultimately death if not managed properly. Current therapeutic approach to hypertension management involves the use of drugs that inhibit excessive activities of renin and angiotensin converting enzyme (ACE), the two main enzymes that control mammalian blood pressure. Since renin catalyzes a single reaction that is the rate‐determining step in the renin–angiotensin system, inhibition of this enzyme activity could be a highly effective strategy for controlling blood pressure without severe negative side effects. However, therapeutic control of renin activity remains difficult with only one approved drug. Some food protein‐derived peptides have been found to inhibit renin activity inhibition, which could offer a drug‐free treatment for hypertension. Therefore, this review provides a summary of recent developments in the advances and efficacy testing of renin‐inhibitory peptides. [ABSTRACT FROM AUTHOR]