RESUMO
In this study, we synthesized a series of seven benzimidazole derivatives incorporating the structural acidic framework of angiotensin II (Ang II) type 1 receptor (AT1R) antagonists (ARA-II) employing a three-step reaction sequence. The chemical structures were confirmed by 1H NMR, 13C NMR and mass spectral data. Through biosimulation, compounds 1-7 were identified as computational safe hits, thus, best candidates underwent ex vivo testing against two distinct mechanisms implicated in hypertension: antagonism of the Ang II type 1 receptor and the blockade of calcium channel. Molecular docking studies helped to understand at the molecular level the dual vasorelaxant effects with the recognition sites of the AT1R and the L-type calcium channel. In an in vivo spontaneously hypertensive rat model (SHR), intraperitoneally administration of compound 1 at 20 mg/kg resulted in a 25 % reduction in systolic blood pressure, demonstrating both ex vivo vasorelaxant action and in vivo antihypertensive multitarget efficacy. ©2024 Elsevier.
Assuntos
Anti-Hipertensivos , Benzimidazóis , Simulação de Acoplamento Molecular , Ratos Endogâmicos SHR , Benzimidazóis/química , Benzimidazóis/farmacologia , Benzimidazóis/síntese química , Animais , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/química , Ratos , Relação Estrutura-Atividade , Pressão Sanguínea/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Receptor Tipo 1 de Angiotensina/metabolismo , Estrutura Molecular , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/síntese química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Bloqueadores dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/síntese química , Bloqueadores dos Canais de Cálcio/química , Canais de Cálcio Tipo L/metabolismoRESUMO
More than 1 billion people worldwide suffer from hypertension; therefore, hypertension management has been categorized as a global health priority. Losartan potassium (LP) is an antihypertensive drug with a limited oral bioavailability of about 33% since it undergoes the initial metabolic cycle. Thus, nasal administration is a unique route to overcome first-pass metabolism. The investigation focused on the potential effects of LP-loaded spanlastic vesicles (SNVs) on LP pharmacodynamics and pharmacokinetic parameters, utilizing a thin-film hydration methodology established on a 3122 full factorial design. Entrapment efficiency (EE%) ranged from 39.8 ± 3.87.8 to 83.8 ± 2.92% for LP-SNVs. Vesicle size (VS) varied from 205.5 ± 6.5.10 to 445.1 ± 13.52 nm, and the percentage of LP released after 8 h (Q8h) ranged from 30.8 ± 3.10 to 68.8 ± 1.45%. LP permeated through the nasal mucosa during 24 h and flocculated from 194.1 ± 4.90 to 435.3 ± 13.53 µg/cm2. After twenty-four hours, the optimal LP-SNVs in-situ gel showed 2.35 times more permeation through the nasal mucosa than the LP solution. It also lowered systolic blood pressure, so it is thought to be better than the reference formulation in terms of pharmacodynamics. The pharmacokinetics studies demonstrated that the intranasal LP-SNVs gel boosted its bioavailability approximately 6.36 times compared to the oral LP solution. Our research showed that intranasal LP-SNVs could be a good nanoplatform because they are well-tolerated and have possible pharmacokinetics and pharmacodynamics.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II , Hipertensão , Losartan , Sistemas de Liberação de Fármacos por Nanopartículas , Animais , Ratos , Administração Intranasal , Angiotensina II/farmacocinética , Angiotensina II/administração & dosagem , Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Anti-Hipertensivos/farmacocinética , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/farmacologia , Disponibilidade Biológica , Pressão Sanguínea/efeitos dos fármacos , Química Farmacêutica/métodos , Géis/química , Géis/farmacologia , Hipertensão/tratamento farmacológico , Losartan/farmacocinética , Losartan/administração & dosagem , Losartan/farmacologia , Nanopartículas/química , Mucosa Nasal/metabolismo , Mucosa Nasal/efeitos dos fármacos , Tamanho da Partícula , Ratos Wistar , Sistemas de Liberação de Fármacos por Nanopartículas/química , Sistemas de Liberação de Fármacos por Nanopartículas/farmacologiaRESUMO
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.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II , Anti-Hipertensivos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Antagonistas de Receptores de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/química , Anti-Hipertensivos/química , SolubilidadeRESUMO
Sartans are a group of pharmaceuticals widely used to regulate blood pressure. Their concentration levels were monitored in 80 wastewater treatment plants (WWTP) in the Baltic Sea Region, reached from limit of detection up to 6 µg/L. The concentrations were significantly different in different countries, but consistent within the respective country. The degradation of sartans (losartan, valsartan, irbesartan) in moving bed biofilm reactors (MBBRs) that utilize biofilms grown on mobile carriers to treat wastewater was investigated for the first time, and compared with the degradation in a conventional activated sludge (CAS) treatment plant. The results showed the formation of six microbial transformation products (TPs) of losartan, four of valsartan, and four of irbesartan in biological wastewater treatment. Four of these metabolites have not been described in the literature before. Chemical structures were suggested and selected TPs were verified and quantified depending on availability of true standards. Valsartan acid was a common TP of losartan, valsartan, and irbesartan. Losartan and irbesartan also shared one TP: losartan/irbesartan TP335. Based on the mass balance analysis, losartan carboxylic acid is the main TP of losartan, and valsartan acid is the main TP of valsartan during the biotransformation process. For irbesartan, TP447 is likely to be the main TP, as its peak areas were two orders of magnitude higher than those of all the other detected TPs of this compound. The effects of adapting biofilms to different biological oxygen demand (BOD) loading on the degradation of sartans as well as the formation of their TPs were investigated. Compared to feeding a poor substrate (pure effluent wastewater from a CAS), feeding with richer substrate (1/3 raw and 2/3 effluent wastewater) promoted the metabolism of most compounds (co-metabolization). However, the addition of raw wastewater inhibited some metabolic pathways of other compounds, such as from losartan/irbesartan to TP335 (competitive inhibition). The formation of irbesartan TP447 did not change with or without raw wastewater. Finally, the sartans and their TPs were investigated in a full-scale CAS wastewater treatment plant (WWTP). The removal of losartan, valsartan, and irbesartan ranged from 3.0 % to 72% and some of the transformation products (TPs) from human metabolism were also removed in the WWTP. However, some of the sartan TPs, i.e., valsartan acid, losartan carboxylic acid, irbesartan TP443 and losartan TP453, were formed in the WWTP. Relative high amounts of especially losartan carboxylic acid, which was detected with concentrations up to 2.27 µg/L were found in the effluent.
Assuntos
Poluentes Químicos da Água , Purificação da Água , Humanos , Losartan/análise , Bloqueadores do Receptor Tipo 1 de Angiotensina II/análise , Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Irbesartana/análise , Águas Residuárias , Pressão Sanguínea , Esgotos , Valsartana/análise , Biofilmes , Poluentes Químicos da Água/químicaRESUMO
BACKGROUND: Despite research on the molecular bases of Alzheimer's disease (AD), effective therapies against its progression are still needed. Recent studies have shown direct links between AD progression and neurovascular dysfunction, highlighting it as a potential target for new therapeutics development. In this work, we screened and evaluated the inhibitory effect of natural compounds from native Peruvian plants against tau protein, amyloid beta, and angiotensin II type 1 receptor (AT1R) pathologic AD markers. METHODS: We applied in silico analysis, such as virtual screening, molecular docking, molecular dynamics simulation (MD), and MM/GBSA estimation, to identify metabolites from Peruvian plants with inhibitory properties, and compared them to nicotinamide, telmisartan, and grapeseed extract drugs in clinical trials. RESULTS: Our results demonstrated the increased bioactivity of three plants' metabolites against tau protein, amyloid beta, and AT1R. The MD simulations indicated the stability of the AT1R:floribundic acid, amyloid beta:rutin, and tau:brassicasterol systems. A polypharmaceutical potential was observed for rutin due to its high affinity to AT1R, amyloid beta, and tau. The metabolite floribundic acid showed bioactivity against the AT1R and tau, and the metabolite brassicasterol showed bioactivity against the amyloid beta and tau. CONCLUSIONS: This study has identified molecules from native Peruvian plants that have the potential to bind three pathologic markers of AD.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Descoberta de Drogas , Compostos Fitoquímicos/farmacologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Humanos , Simulação de Acoplamento Molecular , Peru , Compostos Fitoquímicos/química , Plantas/química , Receptor Tipo 1 de Angiotensina/metabolismo , Proteínas tau/antagonistas & inibidores , Proteínas tau/metabolismoRESUMO
Hypertension is one of the most common diseases nowadays and is still the major cause of premature death despite of the continuous discovery of novel therapeutics. The discovery of the Renin Angiotensin System (RAS) unveiled a path to develop efficient drugs to fruitfully combat hypertension. Several compounds that prevent the Angiotensin II hormone from binding and activating the AT1R, named sartans, have been developed. Herein, we report a comprehensive review of the synthetic paths followed for the development of different sartans since the discovery of the first sartan, Losartan.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/síntese química , Desenho de Fármacos , Receptor Tipo 1 de Angiotensina/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Animais , Humanos , Pró-Fármacos/síntese química , Pró-Fármacos/químicaRESUMO
Physicochemical properties, in particular solubility and the associated bioavailability, are key factors in determining efficacy of poorly water-soluble drugs, which constitute 40% of new drugs in the market, and improving them is an important challenge for modern pharmacy. A recent strategy to achieve this goal is formation of stable co-amorphous solid dispersions with co-formers of low molecular weight. Here, the amorphization strategy was applied for low-soluble anti-hypertensive valsartan (VAL), an angiotensin II receptor blocker, and nicotinamide, which exhibits lung- and cardio-protective effects. Through interactions with the renin-angiotensin-aldosteron system, VAL may be used to treat both hypertension and the current pandemic coronavirus SARS-CoV-2 infection. Using mechanochemical and liquid- and solid-state approaches, solvated co-amorphous solid dispersions of VAL with nicotinamide were obtained. They were characterized by spectroscopic, thermal, and X-ray analyses. The density functional theory, quantum theory of atoms in molecules, and non-covalent interaction index calculations revealed the presence of two types of hydrogen bonds between VAL and NIC (i.e., N-H···O and O-H···O). One of them had a partially covalent character, which caused conformational changes in the flexible VAL molecule, restricting contribution of the tetrazolyl N-H donor and thus limiting the possibility of co-crystal formation. The recognized VAL/NIC1- and VAL/NIC2-type heterodimeric interactions were responsible for the excellent durability of the solid compositions and up to 24-fold better solubility than VAL alone. The synthesized dispersions constitute a new class of dually acting drugs, containing an active pharmaceutical ingredient (VAL) and supporting nutraceutical (nicotinamide).
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Anti-Hipertensivos/química , Tratamento Farmacológico da COVID-19 , Química Farmacêutica/métodos , Portadores de Fármacos/química , Niacinamida/química , Valsartana/química , Anti-Hipertensivos/síntese química , Disponibilidade Biológica , Varredura Diferencial de Calorimetria , Composição de Medicamentos , Humanos , Ligação de Hidrogênio , Espectroscopia de Ressonância Magnética , Microscopia Eletrônica de Varredura , Teoria Quântica , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios XRESUMO
Telmisartan (TLM) is a potent antihypertensive drug with pH-dependent aqueous solubility. This work aimed to enhance the solubility and dissolution rate of TLM by the co-amorphous drug amino acid (AA) approach by combining TLM, with different types and ratios of AAs. The co-amorphous TLM-AA blends were prepared by freeze-drying and investigated for solid-state characteristics like the dissolution rate enhancement of TLM. Among the prepared co-amorphous formulations, TLM-arginine (ARG) exhibited the greatest enhancement in solubility with increasing the molar ratio of ARG. The TLM-ARG at 1:2 ratio showed about a 57-fold increase in solubility of TLM and the highest dissolution percentage in phosphate buffer (pH7.5) (100% in 20 minutes) compared to both crystalline TLM (20% in 60 min) and physical mixture. Powder XRD, DSC, FTIR analysis and SEM demonstrated the formation of amorphous form within the co-amorphous formulations. Only TLM:ARG (1:0.5) were stable at (40°C, 75% RH) for a minimum of 90 days. In conclusion, ARG was able to stabilize the amorphous form of TLM and enhances its aqueous solubility and dissolution. The 1:2 w/w ratio of TLM-ARG co-amorphous showed the best solubility and dissolution rate while the 1:0.5 w/w ratio showed the best stability.
Assuntos
Aminoácidos/química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Telmisartan/administração & dosagem , Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Soluções Tampão , Varredura Diferencial de Calorimetria , Composição de Medicamentos , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Solubilidade , Telmisartan/química , Difração de Raios XRESUMO
Natural products have failed to meet the urgent need for drug discovery in recent decades due to limited resources, necessitating new strategies for re-establishing the key role of natural products in hit screening. This work introduced DNA-encoding techniques into the synthesis of phenolic acid-focused libraries containing 32â¯000 diverse compounds. Online selection of the library using immobilized angiotensin II type I receptor (AT1R) resulted in seven phenolic acid derivatives. The half-maximal concentration (IC50) of hit 1 for the right shift of the [125I]-Sar1-AngII competition curve was 19.6 nM. Pharmacological examination of renovascular hypertensive rats demonstrated that hit 1 significantly lowered the blood pressure of the animals without changing their heart rates. These results were used to create a general strategy for rapid and unbiased discovery of hits derived from natural products with high throughput and efficiency.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Produtos Biológicos/farmacologia , Receptor Tipo 1 de Angiotensina/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/metabolismo , Animais , Produtos Biológicos/química , Produtos Biológicos/metabolismo , DNA/química , Descoberta de Drogas , Ligantes , Masculino , Oligodesoxirribonucleotídeos/química , Ligação Proteica , Ratos Sprague-Dawley , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologiaRESUMO
Hypertension treatment is a current therapeutic priority as there is a constantly increasing part of the population that suffers from this risk factor, which may lead to cardiovascular and encephalic episodes and eventually to death. A number of marketed medicines consist of active ingredients that may be relatively potent; however, there is plenty of room to enhance their pharmacological profile and therapeutic index by improving specific physicochemical properties. In this work, we focus on a class of blood pressure regulators, called sartans, and we present the computational scheme for the pharmacological improvement of irbesartan (IRB) as a representative example. IRB has been shown to exert increased pharmacological action compared with other sartans, but it appears to be highly lipophilic and violates Lipinski rule (MLogP >4.15). To circumvent this drawback, proper hydrophilic molecules, such as cyclodextrins, can be used as drug carriers. This chapter describes the combinatory use of computational methods, namely molecular docking, quantum mechanics, molecular dynamics, and free energy calculations, to study the interactions and the energetic contributions that govern the IRB:cyclodextrin association. We provide a detailed computational protocol, which aims to assist the improvement of the pharmacological properties of sartans. This protocol can also be applied to any other drug molecule with diminished hydrophilic character.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II , Portadores de Fármacos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , beta-Ciclodextrinas , Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacocinética , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Interações Hidrofóbicas e Hidrofílicas , beta-Ciclodextrinas/química , beta-Ciclodextrinas/farmacocinéticaRESUMO
Antagonists of the AT1receptor (AT1R) are beneficial molecules that can prevent the peptide hormone angiotensin II from binding and activating the specific receptor causing hypertension in pathological states. This review article summarizes the multifaced applications of solid and liquid state high resolution nuclear magnetic resonance (NMR) spectroscopy in antihypertensive commercial drugs that act as AT1R antagonists. The 3D architecture of these compounds is explored through 2D NOESY spectroscopy and their interactions with micelles and lipid bilayers are described using solid state 13CP/MAS, 31P and 2H static solid state NMR spectroscopy. Due to their hydrophobic character, AT1R antagonists do not exert their optimum profile on the AT1R. Therefore, various vehicles are explored so as to effectively deliver these molecules to the site of action and to enhance their pharmaceutical efficacy. Cyclodextrins and polymers comprise successful examples of effective drug delivery vehicles, widely used for the delivery of hydrophobic drugs to the active site of the receptor. High resolution NMR spectroscopy provides valuable information on the physical-chemical forces that govern these drug:vehicle interactions, knowledge required to get a deeper understanding on the stability of the formed complexes and therefore the appropriateness and usefulness of the drug delivery system. In addition, it provides valuable information on the rational design towards the synthesis of more stable and efficient drug formulations.
Assuntos
Anti-Hipertensivos/química , Anti-Hipertensivos/farmacologia , Desenho de Fármacos , Espectroscopia de Ressonância Magnética , Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Ciclodextrinas/química , Ciclodextrinas/farmacologia , Estabilidade de Medicamentos , Bicamadas Lipídicas/química , Espectroscopia de Ressonância Magnética/métodos , Micelas , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Polímeros/química , Receptor Tipo 1 de Angiotensina/química , Solventes , Relação Estrutura-AtividadeRESUMO
Angiotensin II type 1 receptor (AT1R) blockers (ARBs) are among the most prescribed drugs. However, ARB effectiveness varies widely, which may be due to non-synonymous single nucleotide polymorphisms (nsSNPs) within the AT1R gene. The AT1R coding sequence contains over 100 nsSNPs; therefore, this study embarked on determining which nsSNPs may abrogate the binding of selective ARBs. The crystal structure of olmesartan-bound human AT1R (PDB:4ZUD) served as a template to create an inactive apo-AT1R via molecular dynamics simulation (n = 3). All simulations resulted in a water accessible ligand-binding pocket that lacked sodium ions. The model remained inactive displaying little movement in the receptor core; however, helix 8 showed considerable flexibility. A single frame representing the average stable AT1R was used as a template to dock Olmesartan via AutoDock 4.2, MOE, and AutoDock Vina to obtain predicted binding poses and mean Boltzmann weighted average affinity. The docking results did not match the known pose and affinity of Olmesartan. Thus, an optimization protocol was initiated using AutoDock 4.2 that provided more accurate poses and affinity for Olmesartan (n = 6). Atomic models of 103 of the known human AT1R polymorphisms were constructed using the molecular dynamics equilibrated apo-AT1R. Each of the eight ARBs was then docked, using ARB-optimized parameters, to each polymorphic AT1R (n = 6). Although each nsSNP has a negligible effect on the global AT1R structure, most nsSNPs drastically alter a sub-set of ARBs affinity to the AT1R. Alterations within N298 -L314 strongly effected predicted ARB affinity, which aligns with early mutagenesis studies. The current study demonstrates the potential of utilizing in silico approaches towards personalized ARB therapy. The results presented here will guide further biochemical studies and refinement of the model to increase the accuracy of the prediction of ARB resistance in order to increase overall ARB effectiveness.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Imidazóis/uso terapêutico , Medicina de Precisão , Tetrazóis/uso terapêutico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Humanos , Imidazóis/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Polimorfismo de Nucleotídeo Único , Receptor Tipo 1 de Angiotensina/genética , Reprodutibilidade dos Testes , Tetrazóis/químicaRESUMO
During the last decades, much attention has been focused on SNEDDS approach to resolve concerns of BCS II class drugs with accentuation on upgrading the solubility and bioavailability. The present hypothesis confirms the theory that SNEDDS can reduce the impact of food on Candesartan solubilization, thereby offering the potential for improved oral delivery without co-administration with meals. The present studies describe quality-by-design-based development and characterization of Candesartan loaded SNEDDS for improving its pharmacodynamic potential. D-optimal mixture design was used for systematic optimization of SNEDDS, which showed globule size of 13.91 nm, more rapid drug release rate of >90% in 30 min and 16 s for self-emulsification. The optimized formulations were extensively evaluated, where an in vitro drug release study indicated up to 1.99- and 1.10-fold enhancement in dissolution rate from SNEDDS over pure drug and marketed tablet. In vivo pharmacodynamic investigation also showed superior antihypertensive potential of SNEDDS in normalizing serum lipid levels as compared to pure drug and marketed tablet that was executed on male Wistar rats. Overall, this paper reports successful systematic development of candesartan-loaded SNEDDS with distinctly improved biopharmaceutical performance. This research work interpreted a major role of SNEDDS for enhancing the rate of dissolution and bioavailability of poorly water soluble drugs.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Benzimidazóis/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Desenho de Fármacos , Tetrazóis/administração & dosagem , Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Benzimidazóis/química , Benzimidazóis/farmacologia , Disponibilidade Biológica , Compostos de Bifenilo , Relação Dose-Resposta a Droga , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Emulsões , Excipientes/química , Interações Alimento-Droga , Masculino , Ratos Wistar , Solubilidade , Tetrazóis/química , Tetrazóis/farmacologiaAssuntos
Enzima de Conversão de Angiotensina 2/antagonistas & inibidores , Antivirais , Infecções por Coronavirus/tratamento farmacológico , Coronavirus/efeitos dos fármacos , Receptores Virais , Bloqueadores do Receptor Tipo 1 de Angiotensina II/síntese química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/isolamento & purificação , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Enzima de Conversão de Angiotensina 2/fisiologia , Inibidores da Enzima Conversora de Angiotensina/síntese química , Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/isolamento & purificação , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Antivirais/síntese química , Antivirais/química , Antivirais/isolamento & purificação , Antivirais/uso terapêutico , COVID-19/imunologia , COVID-19/virologia , Coronavirus/fisiologia , Humanos , Imunidade/efeitos dos fármacos , Imunidade/fisiologia , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Coronavírus da Síndrome Respiratória do Oriente Médio/fisiologia , Receptor Tipo 1 de Angiotensina/fisiologia , Receptores Virais/antagonistas & inibidores , Receptores Virais/efeitos dos fármacos , Receptores Virais/fisiologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia , Tratamento Farmacológico da COVID-19RESUMO
The active hormone of the renin-angiotensin system (RAS), angiotensin II (Ang II), is involved in several human diseases, driving the development and clinical use of several therapeutic drugs, mostly angiotensin I converting enzyme (ACE) inhibitors and angiotensin receptor type I (AT1R) antagonists. However, angiotensin peptides can also bind to receptors different from AT1R, in particular, angiotensin receptor type II (AT2R), resulting in biological and physiological effects different, and sometimes antagonistic, of their binding to AT1R. In the present Perspective, the components of the RAS and the therapeutic tools developed to control it will be reviewed. In particular, the characteristics of AT2R and tools to modulate its functions will be discussed. Agonists or antagonists to AT2R are potential therapeutics in cardiovascular diseases, for agonists, and in the control of pain, for antagonists, respectively. However, controlling their binding properties and their targeting to the target tissues must be optimized.
Assuntos
Bloqueadores do Receptor Tipo 2 de Angiotensina II/administração & dosagem , Bloqueadores do Receptor Tipo 2 de Angiotensina II/metabolismo , Sistemas de Liberação de Medicamentos/tendências , Receptor Tipo 2 de Angiotensina/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/metabolismo , Bloqueadores do Receptor Tipo 2 de Angiotensina II/química , Animais , Sistemas de Liberação de Medicamentos/métodos , Humanos , Receptor Tipo 1 de Angiotensina/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologiaRESUMO
Controlled release formulations are administered once a day and reduce frequency of dose and ensuring patient's compliance. In the current research controlled release matrices of losartan potassium formulated with polymeric combinations of ethocel grade 7 with carbopol 934P NF using different concentrations of polymers. In some polymeric tablets, Co-excipients like CMC, Starch, HPMC was added by replacing of 10% of filler in formulations at 10:5. Tablets were prepared by direct compression method and evaluated for physicochemical characteristics. USP Method-1 (rotating basket method) was used to carry out dissolution study in phosphate buffer pH 6.8. Drug release kinetics determined and comparison of dissolution patterns was done with reference tablets. The polymeric combinations well retarded drug release and drug was released by anamolous non-fickian diffusion mechanism. Dissolution profiles of tested tablets and reference tablets were found not similar. Drug release rate was increased by co-excipients. It was concluded from this research work that this polymeric combination can be used efficiently in designing of controlled release martices.
Assuntos
Acrilatos/química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Celulose/análogos & derivados , Portadores de Fármacos , Losartan/química , Celulose/química , Preparações de Ação Retardada , Difusão , Composição de Medicamentos , Liberação Controlada de Fármacos , Excipientes/química , Cinética , Modelos Químicos , Solubilidade , ComprimidosRESUMO
Cardiovascular diseases and hypertension in particular are major health risks worldwide and the improvement on their treatment will be beneficial for the human health. AT1R antagonists belong to the sartans family that targets the renin-angiotensin aldosterone system (RAAS) through blocking the hormone angiotensin II to exert its detrimental effects in pathological states. As a consequence, they are beneficial to treat hypertension, diabetes related kidney failure and hyperaemic episodes. Long unbiased Molecular Dynamics (MD) simulations are performed in order to explore candesartan's possible 2D and 3D diffusion mechanisms towards AT1R receptor. 3D diffusion mechanism is referred to the direct binding of the AT1 antagonist candesartan to the AT1R 3D structure (PDB ID: 4YAY). 2D diffusion mechanism involves first, the incorporation of candesartan in the bilayer core and then its localization on the AT1R binding cavity, through a diffusion mechanism. The obtained results indicate that membranes interact significantly with the neutral form of candesartan, which is indeed approaching the receptors' active site through diffusion via the lipids. On the other hand, the deprotonated form of the drug is interacting with AT1R's extracellular loop and fails to enter the membrane, pointing out the importance of the pH microenvironment around the receptor. To validate the calculated diffusion coefficients of the drug in the lipid bilayers 2D DOSY NMR experiments were recorded and they were in good agreement. Information on the impact that has the interaction of candesartan with the membrane is very important for the rationally design and development of potent ARBs. Thus, its conformational features as well as its localization in the membrane core have to be thoroughly explored.
Assuntos
Benzimidazóis/química , Benzimidazóis/farmacologia , Receptor Tipo 1 de Angiotensina/efeitos dos fármacos , Tetrazóis/química , Tetrazóis/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Compostos de Bifenilo , Humanos , Hipertensão/tratamento farmacológico , Bicamadas Lipídicas/metabolismo , Espectroscopia de Ressonância Magnética , Membranas/metabolismo , Conformação Molecular , Simulação de Dinâmica Molecular , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 1 de Angiotensina/ultraestrutura , Receptores Acoplados a Proteínas G/efeitos dos fármacos , Receptores Acoplados a Proteínas G/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologiaRESUMO
A series of new 6-substituted aminocarbonyl benzimidazole derivatives with 1, 4-disubsituted or 1, 5-disubsituted indole moiety and benzoic acid moiety were designed, synthesized and pharmacologically evaluated. Most of the synthesized compounds could bind to the AT1 receptor and decrease blood pressure significantly. Notably, 2e and 1h could obviously decrease MBP in a dose dependent manner. The maximal response lowered 57.9⯱â¯2.3â¯mmHg (2e) and 57.6⯱â¯1.9â¯mmHg (1h) of MBP at 10â¯mg/kg after oral administration, and the antihypertensive effect lasted beyond 24â¯h, which performed better than Losartan (Fig. 1). These results indicate that 2e and 1h are effective and long-lasting anti-hypertension drug candidates and deserve further investigation for therapeutic application.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Benzimidazóis/farmacologia , Desenho de Fármacos , Receptor Tipo 1 de Angiotensina/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/síntese química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Animais , Benzimidazóis/síntese química , Benzimidazóis/química , Relação Dose-Resposta a Droga , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Co amorphous systems are supersaturated drug delivery systems which offer a basic platform for delivery of multicomponent adducts (combination of more than one active pharmaceutical ingredient (API)) and/or as a fixed dose combination therapy, in addition to their potential to improve the apparent solubility, dissolution rate and ultimately bioavailability of poorly water soluble APIs. In the present work, a new drug-drug co amorphous system namely valsartan-nifedipine was prepared by quench cooling technique. Prepared co amorphous system was characterized for its solid state behavior with the help of Fourier Transform Infrared spectroscopy (FTIR), Differential Scanning Calorimetry (DSC) and Powder X Ray Diffractometry (PXRD). The optimized co amorphous system was stable for 1â¯month when exposed to accelerated stability condition (40⯱â¯2⯰C and 75⯱â¯5% RH). The improved stability of amorphous nifedipine in co amorphous system was attributed to improved miscibility and intra and intermolecular non-covalent interactions mainly due to presence of hydrogen bonding between valsartan and nifedipine which was studied by FTIR analysis. Co amorphous systems were evaluated by mainly in vitro dissolution and in vivo benefit. In vitro dissolution study showed nearly 5.66 folds and 1.61 folds improvement which was translated to 3.63 and 2.19 times enhancement in vivo Cmax for nifedipine and valsartan respectively.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II , Bloqueadores dos Canais de Cálcio , Nifedipino , Valsartana , Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacocinética , Animais , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacocinética , Combinação de Medicamentos , Composição de Medicamentos , Liberação Controlada de Fármacos , Feminino , Nifedipino/química , Nifedipino/farmacocinética , Ratos Sprague-Dawley , Valsartana/química , Valsartana/farmacocinéticaRESUMO
Fibrosis is a final pathological feature of many chronic diseases, but few interventions are available that specifically target the pathogenesis of fibrosis. The highlights of common cellular and molecular mechanisms of fibrosis facilitate the discovery of effective antifibrotic drugs. The renin-angiotensin system (RAS) plays a central physiological role in the control of blood pressure and fluid homeostasis. Emerging evidence has revealed that activation of RAS was consistently found in fibrotic tissue. At the same time, as more components of the RAS are described, other pot Potential therapeutic targets emerge, so it seems sensible to revisit the contribution of RAS in anti-fibrotic therapy. So far, angiotensin converting enzyme inhibitors (ACEI) and angiotensin II type 1 receptor blockers (ARB) are the main commercial available drugs for intervening RAS. However, RAS inhibitors had lots of limitations in long-term application owing to occurring AngII and aldosterone escape. Over the past decades, natural products have aroused growing attention as potential RAS inhibitors due to their high efficacy and low risk of side effects. In this review, we revisit the contribution of RAS and its new members to anti-fibrotic therapy. Ultimately, we summarize and evaluate the use of natural products including isolated compounds, crude extracts and traditional Chinese herbal formulas to regulate RAS. These natural products can retard tissue fibrosis by targeting different RAS components, which provide us new therapeutic strategies to discover anti-fibrotic drugs.