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
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
Telmisartan (TEL) is an antihypertensive BCS class II drug with low solubility at physiological pH. However, the solubility of TEL increases with the presence of an alkalizer. Electrospinning is one of the most recent techniques for the solubility enhancement studies. In this study, an electrospun orally disintegrating film (ODF) formulation of TEL was developed with L-arginine and polyvinylpyrrolidone K90 (PVP), and its characterization studies were performed. Preformulation studies were performed to investigate possible incompatibilities in the components of formulation with differential scanning calorimetry (DSC) and Fourier transform infrared spectrometer (FT-IR) analyses. ODFs were characterized in terms of drug content and uniformity, mechanical properties, fiber shape and diameter and in vitro dissolution profile. Smooth nanofibers without any beads were obtained. The dissolution rate of the TEL significantly increased. The chosen formulation had acceptable mechanical properties with much faster dissolution compared to the commercially available product. Developed ODF and marketed product were compared with a dissolution study in phosphate-buffered solution (pH 7.4). ODF and marketed product both reached 100% release in the 45th minute, and ODF results showed that ODF had much faster release than marketed product. In this study, TEL ODF formulation was successfully produced and characterized.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/síntese química , Composição de Medicamentos/métodos , Nanofibras/química , Telmisartan/síntese química , Administração Oral , Bloqueadores do Receptor Tipo 1 de Angiotensina II/análise , Nanofibras/análise , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Telmisartan/administração & dosagem , Telmisartan/análise , ViscosidadeAssuntos
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
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
Because of the complex biological networks, many pathologic disorders fail to be treated with a molecule directed towards a single target. Thus, combination therapies are often necessary, but they have many drawbacks. An alternative consists in building molecules intended to interact with multiple targets, called designed multiple ligands. We followed such a strategy in order to treat metabolic syndrome, by setting up molecules directed towards both type 1 angiotensin II (AT1) receptor and peroxisome proliferator-activated receptor-γ (PPAR-γ). For this purpose, many molecules were prepared by merging both pharmacophores following three different strategies. Their ability to activate PPAR-γ and to block AT1 receptors were evaluated in vitro. This strategy led to the preparation of many new PPAR-γ activating and AT1 blocking molecules. Among them, some exhibited both activities, highlighting the convenience of this approach.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Desenho de Fármacos , PPAR gama/agonistas , Bloqueadores do Receptor Tipo 1 de Angiotensina II/síntese química , Animais , Cromanos/síntese química , Cromanos/química , Cromanos/farmacologia , Humanos , Imidazóis/síntese química , Imidazóis/química , Imidazóis/farmacologia , Ligantes , Células MCF-7 , Masculino , Simulação de Acoplamento Molecular , PPAR gama/metabolismo , Ratos Wistar , Receptor Tipo 1 de Angiotensina/metabolismo , Triazóis/síntese química , Triazóis/química , Triazóis/farmacologiaRESUMO
A series of new 5-oxo-1,2,4-oxadiazole derivatives with 1, 4-disubsituted or 1, 5-disubsituted indole group was designed, synthesized, and pharmacologically evaluated. These derivatives displayed high affinities to the AT1 receptor at the same order of magnitude to losartan. The methyl ester with 1, 4-disubsituted indole group, 1 (5.01 ± 1.67 nM) showed high antihypertension activity on spontaneously hypertensive rats (SHRs). Its maximal response lowered 30 mmHg of mean blood pressure (MBP) at 10 mg/kg after oral administration, which was better than irbesartan, and the antihypertensive effect lasted beyond 24 h. These results made 1 deserve further investigation.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Anti-Hipertensivos/farmacologia , Hipertensão/tratamento farmacológico , Administração Oral , Bloqueadores do Receptor Tipo 1 de Angiotensina II/síntese química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Animais , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/química , Benzimidazóis/síntese química , Benzimidazóis/química , Benzimidazóis/farmacologia , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia , Feminino , Irbesartana , Losartan/síntese química , Losartan/química , Losartan/farmacologia , Masculino , Oxidiazóis/síntese química , Oxidiazóis/química , Oxidiazóis/farmacologia , Ratos Endogâmicos SHR , Tetrazóis/síntese química , Tetrazóis/química , Tetrazóis/farmacologiaRESUMO
A series of new angiotensin II (Ang II) receptor 1 antagonists were designed, synthesized and evaluated. All compounds showed nanomolar affinities for the angiotensin II type 1 receptor in radioligand binding assays and could reduce blood pressure significantly in spontaneously hypertensive rats(SHRs). From which, compound 2b displayed higher affinity binding to angiotensin II type 1 receptor at the same order of magnitude to irbesartan with an IC50 value of 1.26 ± 0.08 nM in radioligand binding assays. 2b showed an efficient and long-lasting effect in reducing blood pressure, the maximal reducing responses were 40.62 ± 4.08 mmHg of MBP at 15 mg/kg and 28.39 ± 2.09 mmHg at 10 mg/kg in SHRs, 39.56 ± 4.83 mmHg at 15 mg/kg and 29.05 ± 2.20 mmHg at 10 mg/kg in RHRs, the significant antihypertensive effect lasted beyond 12 h both in SHRs and in RHRs. In the single-dose pharmacokinetic experiments, compound 2b could be absorbed efficiently and metabolized smoothly in Wistar rats after oral administration. The values of Cmax, Tmax, AUC0-72 and MRT0-72 were 885.61 ± 432.7 ng/mL, 5.67 ± 1.51 h, 6110.28 ± 7398.33 ng/mL h and 7.87 ± 2.30 h at 10 mg/kg, 2945.55 ± 1543.67 ng/mL, 4.33 ± 0.82 h, 26473.62 ± 12217.16 ng/mL h and 10.24 ± 6.94 h at 15 mg/kg, 5759.03 ± 1331.75 ng/mL, 5 ± 1.10 h, 89488.44 ± 18413.15 ng/mL·h and 12.89 ± 2.0 h at 30 mg/kg respectively. The T1/2 values of the three groups were similar, about 9-10 h. Compound 2b was distributed into tissues rapidly and extensively after oral administration. The level of it was the highest in the liver, followed by in spleen, kidney, and the lowest in brain. The acute toxicity assays of 2b proved its low acute toxicity with an LD50 value of 1551.71 mg/kg, and no toxicity reaction appeared at dose of 1200.00 mg/kg. These encouraging results make compound 2b an effective, long-lasting and safe anti-hypertensive drug candidate and worthy of further investigation.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/síntese química , Anti-Hipertensivos/farmacocinética , Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Desenho de Fármacos , Ratos , Ratos Endogâmicos SHR , Ratos Wistar , Receptor Tipo 1 de Angiotensina/metabolismo , Relação Estrutura-Atividade , Distribuição TecidualRESUMO
During the process development for multigram-scale synthesis of olmesartan medoxomil (OM), two principal regioisomeric process-related impurities were observed along with the final active pharmaceutical ingredient (API). The impurities were identified as N-1- and N-2-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl derivatives of OM. Both compounds, of which N-2 isomer of olmesartan dimedoxomil is a novel impurity of OM, were synthesized and fully characterized by differential scanning calorimetry (DSC), infrared spectroscopy (IR), nuclear magnetic resonance spectroscopy (NMR) and high-resolution mass spectrometry/electrospray ionization (HRMS/ESI). Their ¹H, (13)C and (15)N nuclear magnetic resonance signals were fully assigned. The molecular structures of N-triphenylmethylolmesartan ethyl (N-tritylolmesartan ethyl) and N-tritylolmesartan medoxomil, the key intermediates in OM synthesis, were solved and refined using single-crystal X-ray diffraction (SCXRD). The SCXRD study revealed that N-tritylated intermediates of OM exist exclusively as one of the two possible regioisomers. In molecular structures of these regioisomers, the trityl substituent is attached to the N-2 nitrogen atom of the tetrazole ring, and not to the N-1 nitrogen, as has been widely reported up to the present. This finding indicates that the reported structural formula of N-tritylolmesartan ethyl and N-tritylolmesartan medoxomil, as well as their systematic chemical names, must be revised. The careful analysis of literature spectroscopic data for other sartan intermediates and their analogs with 5-(biphenyl-2-yl)tetrazole moiety showed that they also exist exclusively as N-2-trityl regioisomers.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/análise , Bloqueadores do Receptor Tipo 1 de Angiotensina II/síntese química , Contaminação de Medicamentos , Olmesartana Medoxomila/análise , Olmesartana Medoxomila/síntese química , Tetrazóis/química , Cromatografia Líquida de Alta Pressão , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Espectrometria de Massas por Ionização por Electrospray , Espectrofotometria Infravermelho , Difração de Raios XRESUMO
The 2-[(18)F]fluoro-3-pent-4-yn-1-yloxypyridine ([(18)F]FPyKYNE) analog of the potent non-peptide angiotensin II type 1 receptor (AT1R) blocker losartan was produced via click chemistry linking [(18)F]FPyKYNE to azide-modified tetrazole-protected losartan followed by TFA deprotection. Preliminary small animal imaging with positron emission tomography (PET) in rats displayed high uptake in the kidneys with good contrast to surrounding tissue. Rat metabolism displayed the presence of 23% unchanged tracer in plasma at 30 min. Upon co-administration with AT1R blocker candesartan (2.5, 5 and 10 mg/kg), a dose-dependent reduction (47-65%) in tracer uptake was observed in the kidney, while no difference was observed following AT2R blocker PD123,319 (5 mg/kg), indicating binding selectivity for AT1R over AT2R and potential for imaging AT1R using PET.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/síntese química , Losartan/química , Receptor Tipo 1 de Angiotensina/química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Benzimidazóis/farmacologia , Compostos de Bifenilo , Radioisótopos de Flúor/química , Rim/diagnóstico por imagem , Rim/efeitos dos fármacos , Rim/metabolismo , Losartan/síntese química , Losartan/farmacologia , Masculino , Tomografia por Emissão de Pósitrons , Piridinas/química , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/química , Ratos , Ratos Sprague-Dawley , Receptor Tipo 1 de Angiotensina/metabolismo , Tetrazóis/química , Tetrazóis/farmacologiaRESUMO
Both 6-substituted aminocarbonyl and acylamino benzimidazole derivatives were designed and synthesized as nonpeptidic angiotensin II AT1 receptor antagonists. Compounds 6f, 6g, 11e, 11f, 11g, and 12 showed nanomolar AT1 receptor binding affinity and high AT1 receptor selectivity over AT2 receptor in a preliminary pharmacological evaluation. Among them, the two most active compounds 6f (AT1 IC50 = 3 nM, AT2 IC50 > 10,000 nM, PA2 = 8.51) and 11g (AT1 IC50 = 0.1 nM, AT2 IC50 = 149 nM, PA2 = 8.43) exhibited good antagonistic activity in isolated rabbit aortic strip functional assay. In addition, they were orally active AT1 receptor antagonists in spontaneous hypertensive rats.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/síntese química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Benzimidazóis/farmacologia , Receptor Tipo 1 de Angiotensina/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Benzimidazóis/síntese química , Benzimidazóis/química , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Receptor Tipo 1 de Angiotensina/química , Relação Estrutura-AtividadeRESUMO
INTRODUCTION: For two decades a class of pharmaceutical molecules with proved beneficial therapeutic properties, especially in hypertension, has been introduced in the market aiming to specifically prevent the detrimental effects of the peptide hormone Angiotensin II at the AT1 receptor. The prototype of this class was losartan and based on its structure, several drugs were launched and also called 'Sartans'. New structural features on these molecules can provide multi-target properties in the RAS or other systems. New methodologies were developed for the treatment of hypertension utilizing either AT1 antagonists alone or as cocktails. AREAS COVERED: In this review article, authors aim to cover information provided by patents of the years 2008 - 2012. The rationale of writing this review article is to cover the most important patents which can forward the field with new important discoveries. EXPERT OPINION: From the patent investigation it is clear that new areas on the subject are still offered for new discoveries. New structural features can be still considered in the synthetic compounds that can advance the knowledge and beneficial effects on diseases related to Angiotensin II and AT1 receptor. There is era also for new formulations (i.e., cyclodextrins, polymers and liposomes). The multitarget approach can be further strengthened and more combinations can be sought in the rational drug design for seeking cocktails. Furthermore, the revealing of the complexity of the RAS offers new avenues for novel targets and this must not be overlooked.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/síntese química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Química Farmacêutica , Combinação de Medicamentos , Descoberta de Drogas , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Modelos Moleculares , Oxazóis/farmacologia , Patentes como Assunto , Sistema Renina-Angiotensina/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Telmisartan is an antihypertensive drug and is a specific angiotensin II receptor (AT1) antagonist. According to European Pharmacopoeia 7 Edition 2008 telmisartan quality standard, there are seven impurities in telmisartan. Impurity B which is not available commercially and no synthetic method is published so far. We report herein the first synthesis of impurity B. The structure of impurity B was confirmed by 1H NMR, 13C NMR and MS data. These findings should be important for quality control purposes in the manufacture and quality control of telmisartan.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/síntese química , Benzimidazóis/síntese química , Benzoatos/síntese química , Cromatografia em Gel , Cromatografia em Camada Fina , Contaminação de Medicamentos , Indicadores e Reagentes , Controle de Qualidade , Solventes , Espectrometria de Massas por Ionização por Electrospray , TelmisartanRESUMO
In the present work, a facile and efficient route for the synthesis of a series of N-substituted imidazole derivatives is described. Docking studies have revealed that N-substituted imidazole derivatives based on (E)-urocanic acid may be potential antihypertensive leads. Therefore, new AT1 receptor blockers bearing either the benzyl or the biphenylmethyl moiety at the N-1 or N-3 position, either the (E)-acrylate or the propanoate fragment and their related acids at the C-4 position as well as a halogen atom at the C-5 position of the imidazole ring, were synthesized. The newly synthesized analogues were evaluated for binding to human AT1 receptor. The biological results showed that this class of molecules possesses moderate or no activity, thus not always confirming high docking scores. Nonetheless, important conclusions can be derived for their molecular basis of their mode of action and help medicinal chemists to design and synthesize more potent ones. An aliphatic group as in losartan seems to be important for enhancing binding affinity and activity.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/síntese química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/farmacologia , Imidazóis/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Anti-Hipertensivos/química , Desenho de Fármacos , Humanos , Imidazóis/síntese química , Imidazóis/química , Simulação de Acoplamento Molecular , Receptor Tipo 1 de Angiotensina/metabolismo , Relação Estrutura-Atividade , Ácido Urocânico/química , Ácido Urocânico/metabolismoRESUMO
A series of symmetrically bis-substituted imidazole analogs bearing at the N-1 and N-3 two biphenyl moieties ortho substituted either with tetrazole or carboxylate functional groups was designed based on docking studies and utilizing for the first time an extra hydrophobic binding cleft of AT1 receptor. The synthesized analogs were evaluated for their in vitro antagonistic activities (pA2 values) and binding affinities (-logIC50 values) to the Angiotensin II AT1 receptor. Among them, the potassium (-logIC50 = 9.04) and the sodium (-logIC50 = 8.54) salts of 4-butyl-N,N'-bis{[2'-(2H-tetrazol-5-yl)biphenyl-4-yl]methyl}imidazolium bromide (12a and 12b, respectively) as well as its free acid 11 (-logIC50 = 9.46) and the 4-butyl-2-hydroxymethyl-N,N'-bis{[2'-(2H-tetrazol-5-yl)biphenyl-4-yl]methyl}imidazolium bromide (14) (-logIC50 = 8.37, pA2 = 8.58) showed high binding affinity to the AT1 receptor and high antagonistic activity (potency). The potency was similar or even superior to that of Losartan (-logIC50 = 8.25, pA2 = 8.25). On the contrary, 2-butyl-N,N'-bis{[2'-[2H-tetrazol-5-yl)]biphenyl-4-yl]methyl}imidazolium bromide (27) (-logIC50 = 5.77) and 2-butyl-4-chloro-5-hydroxymethyl-N,N'-bis{[2'-[2H-tetrazol-5-yl)]biphenyl-4-yl]methyl}imidazolium bromide (30) (-logIC50 = 6.38) displayed very low binding affinity indicating that the orientation of the n-butyl group is of primary importance. Docking studies of the representative highly active 12b clearly showed that this molecule has an extra hydrophobic binding feature compared to prototype drug Losartan and it fits to the extra hydrophobic cavity. These results may contribute to the discovery and development of a new class of biologically active molecules through bis-alkylation of the imidazole ring by a convenient and cost effective synthetic strategy.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Desenho de Fármacos , Imidazóis/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/síntese química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Relação Dose-Resposta a Droga , Humanos , Imidazóis/síntese química , Imidazóis/química , Modelos Moleculares , Estrutura Molecular , Teoria Quântica , Relação Estrutura-AtividadeRESUMO
Synthesis of a new ester prodrug of olmesartan, olmesartan hexetil (1), is described. It is in vitro stabilities and in vivo pharmacokinetics (PK) were evaluated. It showed high stability in simulated gastric juice, and was rapidly hydrolyzed to olmesartan in rat liver microsomes and rat plasma in vitro. C(max) and AUC(last) for olmesartan were significantly increased in case of hexetil prodrug, compared with olmesartan medoxomil. Olmesartan hexetil is proposed to be an efficient prodrug of olmesartan with markedly increased oral bioavailability.
Assuntos
Anti-Hipertensivos/farmacocinética , Imidazóis/síntese química , Imidazóis/farmacocinética , Pró-Fármacos/síntese química , Pró-Fármacos/farmacocinética , Tetrazóis/síntese química , Tetrazóis/farmacocinética , Bloqueadores do Receptor Tipo 1 de Angiotensina II/síntese química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacocinética , Animais , Disponibilidade Biológica , Descoberta de Drogas , Estabilidade de Medicamentos , Ésteres/síntese química , Suco Gástrico/química , Suco Gástrico/metabolismo , Imidazóis/sangue , Masculino , Microssomos Hepáticos/metabolismo , Ratos , Ratos Sprague-Dawley , Tetrazóis/sangueRESUMO
Identification of a series of imidazo[4,5-c]pyridin-4-one derivatives that act as dual angiotensin II type 1 (AT1) receptor antagonists and peroxisome proliferator-activated receptor-γ (PPARγ) partial agonists is described. Starting from a known AT1 antagonist template, conformational restriction was introduced by incorporation of an indane ring that when combined with appropriate substitution at the imidazo[4,5-c]pyridin-4-one provided novel series 5 possessing the desired dual activity. The mode of interaction of this series with PPARγ was corroborated through the X-ray crystal structure of 12b bound to the human PPARγ ligand binding domain. Modulation of activity at both receptors through substitution at the pyridone nitrogen led to the identification of potent dual AT1 antagonists/PPARγ partial agonists. Among them, 21b was identified possessing potent dual pharmacology (AT1 IC(50) = 7 nM; PPARγ EC(50) = 295 nM, 27% max) and good ADME properties.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/síntese química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , PPAR gama/metabolismo , Piridinas/síntese química , Piridinas/farmacologia , Receptor Tipo 1 de Angiotensina/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Benzimidazóis/química , Benzimidazóis/farmacologia , Benzoatos/química , Benzoatos/farmacologia , Cristalografia por Raios X , Humanos , Imidazóis/síntese química , Imidazóis/química , Imidazóis/farmacologia , Concentração Inibidora 50 , Modelos Moleculares , Conformação Molecular , PPAR gama/agonistas , Ligação Proteica/efeitos dos fármacos , Piridinas/química , Piridonas/síntese química , Piridonas/química , Piridonas/farmacologia , TelmisartanRESUMO
A convenient and facile synthesis, in silico docking studies and in vitro biological evaluation of N-substituted 5-butylimidazole derivatives as potent Angiotensin II (ANG II) receptor type 1 (AT1) blockers (ARBs) has been reported in the current study. Our efforts have been directed towards the development of an efficient synthetic route allowing the facile introduction of substituents on the imidazole ring. In particular, a series of imidazole based compounds bearing the biphenyl moiety at the N - 1 position, a halogen atom at the C-4 and polar substituents such as hydroxymethyl, aldo or carboxy group at the C-2 position were designed and synthesized. These compounds were evaluated for binding to human AT1 receptor and for ANG II antagonism in vitro on isolated rat uterus. Among them, 5-butyl-1-[[2'-(2H-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole-2-carboxylic acid (30) exhibited higher binding affinity compared to the other analogues tested (-log IC(50) = 8.46). The latter analogue was also found to be the most active in the rat uterotonic test (pA(2) = 7.83). Importantly, the binding affinity was higher to that of losartan (-log IC(50) = 8.25) indicating the importance of carboxy group at the C-2 position. Experimental findings are in good agreement with docking studies, which were undertaken in order to investigate ligand/AT1 receptor interactions.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/síntese química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Descoberta de Drogas , Imidazóis/síntese química , Imidazóis/farmacologia , Simulação de Acoplamento Molecular , 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 , Técnicas de Química Sintética , Feminino , Células HEK293 , Humanos , Imidazóis/química , Imidazóis/metabolismo , Técnicas In Vitro , Concentração Inibidora 50 , Conformação Proteica , Ratos , Ratos Wistar , Receptor Tipo 1 de Angiotensina/química , Contração Uterina/efeitos dos fármacos , Útero/efeitos dos fármacos , Útero/fisiologiaRESUMO
A series of 6-substituted carbamoyl benzimidazoles were designed and synthesised as new nonpeptidic angiotensin II AT(1) receptor antagonists. The preliminary pharmacological evaluation revealed a nanomolar AT(1) receptor binding affinity for all compounds in the series, and a potent antagonistic activity in an isolated rabbit aortic strip functional assay for compounds 6f, 6g, 6h and 6k was also demonstrated. Furthermore, evaluation in spontaneous hypertensive rats and a preliminary toxicity evaluation showed that compound 6g is an orally active AT(1) receptor antagonist with low toxicity.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/síntese química , Benzimidazóis/química , Desenho de Fármacos , Receptor Tipo 1 de Angiotensina/química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Benzimidazóis/síntese química , Benzimidazóis/farmacologia , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Modelos Moleculares , Ligação Proteica , Coelhos , Ratos , Ratos Endogâmicos SHR , Receptor Tipo 1 de Angiotensina/metabolismo , Relação Estrutura-AtividadeRESUMO
A series of novel angiotensin II type 1 receptor antagonists were prepared. Radioligand binding assay suggested that compounds 1b and 1c could be recognized by the AT(1) receptor with an IC(50) value of 1.6 ± 0.09 nM and 2.64 ± 0.7 nM, respectively. In vivo anti-hypertension experiments showed that compounds (1a, 1b, 1c, 1e) elicited a significant decrease in SBP and DBP of spontaneous hypertensive rats (SHRs). The antihypertensive effects maintained for 10 h, which indicated that these compounds had a favorable blood pressure-lowering effect. Acute toxicity testing suggested that the LD(50) value of compound 1b was 2316.8 mg/kg which was lower than valsartan (LD(50)=307.50 mg/kg) but higher than losartan (LD(50)=2248 mg/kg). So they could be considered as novel anti-hypertension candidates and deserved for further investigation.