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1.
Molecules ; 25(8)2020 Apr 18.
Artículo en Inglés | MEDLINE | ID: mdl-32325695

RESUMEN

Losartan is widely used in clinics to treat cardiovascular related diseases by selectively blocking the angiotensin II type 1 receptors (AT1Rs), which regulate the renin-angiotensin system (RAS). Therefore, monitoring the physiological and pathological biodistribution of AT1R using positron emission tomography (PET) might be a valuable tool to assess the functionality of RAS. Herein, we describe the synthesis and characterization of two novel losartan derivatives PET tracers, [18F]fluoroethyl-losartan ([18F]FEtLos) and [18F]ammoniomethyltrifluoroborate-losartan ([18F]AMBF3Los). [18F]FEtLos was radiolabeled by 18F-fluoroalkylation of losartan potassium using the prosthetic group 2-[18F]fluoroethyl tosylate; whereas [18F]AMBF3Los was prepared following an one-step 18F-19F isotopic exchange reaction, in an overall yield of 2.7 ± 0.9% and 11 ± 4%, respectively, with high radiochemical purity (>95%). Binding competition assays in AT1R-expressing membranes showed that AMBF3Los presented an almost equivalent binding affinity (Ki 7.9 nM) as the cold reference Losartan (Ki 1.5 nM), unlike FEtLos (Ki 2000 nM). In vitro and in vivo assays showed that [18F]AMBF3Los displayed a good binding affinity for AT1R-overexpressing CHO cells and was able to specifically bind to renal AT1R. Hence, our data demonstrate [18F]AMBF3Los as a new tool for PET imaging of AT1R with possible applications for the diagnosis of cardiovascular, inflammatory and cancer diseases.


Asunto(s)
Radioisótopos de Flúor , Losartán/análogos & derivados , Losartán/química , Imagen Molecular , Receptor de Angiotensina Tipo 1/química , Receptor de Angiotensina Tipo 1/metabolismo , Animales , Ratones , Modelos Animales , Imagen Molecular/métodos , Estructura Molecular , Tomografía de Emisión de Positrones , Unión Proteica , Radiofármacos , Distribución Tisular
2.
J Nanosci Nanotechnol ; 18(10): 6765-6775, 2018 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-29954492

RESUMEN

Despite several advancements in the biomedical sciences, an efficient cancer therapy still remains a challenge. Nanomedicines have shown potential to overcome certain roadblocks faced in the existing treatment modalities. Losartan potassium (LP) which is a known vasodilator also exhibits anti fibrolytic and anti-metastatic properties altogether. Further, also being a potential angiotensin II type 1 receptor antagonist, it has been well explored for down regulating tumourogenic biomarkers like VEGF-A (Vascular endothelial growth factor A) and suppression of neovascularization, making it a suitable drug to target for cancer treatment. Besides this, it too reflected the stimulation of pro apoptotic signaling pathways. But due to its lower bioavailability and extensive hepatic metabolism its therapeutic index reduces down. Thus, the present study is focused on designing a nano-delivery system using graphene oxide (GO) as a nano-vehicle and conjugated the LP with it. Then, the successful synthesis of GO and GO-LP nano conjugates were characterized by high-resolution transmission electron microscopy, X-ray diffraction, FTIR and UV visible spectroscopy, confirming the formation of nanosheets. The qualitative morphological evaluation of NB41A3 neuroblastoma cell line treated with bare GO, LP and GO-LP using microscopy and DAPI staining revealed the inhibitory action of GO-LP nano conjugate on cell proliferation. Additionally, the cytotoxicity was also estimated using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), Nitric oxide (NO) and Lactate dehydrogenase (LDH) assays. The results show that GO-LP significantly suppresses the cell viability in comparison to control and bare GO suggesting that the designed system may express its potential to be used with existing chemo drugs for the treatment of neural cancers.


Asunto(s)
Antineoplásicos/uso terapéutico , Grafito/uso terapéutico , Losartán/uso terapéutico , Nanoconjugados/uso terapéutico , Neuroblastoma/tratamiento farmacológico , Bloqueadores del Receptor Tipo 1 de Angiotensina II/química , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Animales , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Grafito/química , Losartán/análogos & derivados , Ratones , Nanoconjugados/química
3.
Pediatr Surg Int ; 32(12): 1103-1114, 2016 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-27670279

RESUMEN

BACKGROUND: Blockade of the renin-angiotensin system (RAS) has been shown to alleviate inflammatory processes in the gastrointestinal tract. The aim of this study was to determine if blockade of the RAS would be effective in an immunologically relevant colitis model, and to compare outcome with an acute colitis model. METHODS: A losartan analog, CCG-203025 (C23H26ClN3O5S) containing a highly polar sulfonic acid moiety that we expected would allow localized mucosal antagonism with minimal systemic absorption was selected as an angiotensin II type 1a receptor antagonist (AT1aR-A). Two colitis models were studied: (1) Acute colitis was induced in 8- to 10-week-old C57BL/6J mice by 2.5 % dextran sodium sulfate (DSS, in drinking water) for 7 days. (2) IL10-/-colitis Piroxicam (200 ppm) was administered orally in feed to 5-week-old IL-10-/-mice (C57BL/6J background) for 14 days followed by enalaprilat (ACE-I), CCG-203025 or PBS administered transanally for 14 days. RESULTS: In the DSS model, weight loss and histologic score for CCG-203025 were better than with placebo. In the IL10-/-model, ACE-I suppressed histologic damage better than CCG-203025. Both ACE-I and CCG-203025 reduced pro-inflammatory cytokines and chemokines. CONCLUSIONS: This study demonstrated the therapeutic efficacy of both ACE-I and AT1aR-A for preventing the development of both acute and immunologically relevant colitis.


Asunto(s)
Colitis/inmunología , Colitis/prevención & control , Losartán/análogos & derivados , Losartán/farmacología , Sistema Renina-Angiotensina/efectos de los fármacos , Enfermedad Aguda , Bloqueadores del Receptor Tipo 1 de Angiotensina II/inmunología , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/inmunología , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Animales , Colitis/patología , Inhibidores de la Ciclooxigenasa/inmunología , Inhibidores de la Ciclooxigenasa/farmacología , Modelos Animales de Enfermedad , Enalaprilato/inmunología , Enalaprilato/farmacología , Losartán/inmunología , Ratones , Ratones Endogámicos C57BL , Piroxicam/inmunología , Piroxicam/farmacología , Sistema Renina-Angiotensina/inmunología
4.
Dig Dis Sci ; 56(9): 2553-65, 2011 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-21399927

RESUMEN

BACKGROUND: Renin-angiotensin system blockade reduces inflammation in several organ systems. Having found a fourfold increase in angiotensin II type Ia receptor expression in a dextran sodium sulfate colitis model, we targeted blockade with angiotensin II type Ia receptor antagonists to prevent colitis development. Because hypotension is a major complication of angiotensin II type Ia receptor antagonists use, we hypothesized that use of angiotensin II type Ia receptor antagonists compounds which lack cell membrane permeability, and thus enteric absorption, would allow for direct enteral delivery at far higher concentrations than would be tolerated systemically, yet retain efficacy. METHODS: Based on the structure of the angiotensin II type Ia receptor antagonist losartan, deschloro-losartan was synthesized, which has extremely poor cell membrane permeability. Angiotensin II type Ia receptor antagonist efficacy was evaluated by determining the ability to block NF-κB activation in vitro. Dextran sodium sulfate colitis was induced in mice and angiotensin II type Ia receptor antagonist efficacy delivered transanally was assessed. RESULTS: In vitro, deschloro-losartan demonstrated near equal angiotensin II type Ia receptor blockade compared to losartan as well as another angiotensin II type Ia receptor antagonist, candesartan. In the dextran sodium sulfate model, each compound significantly improved clinical and histologic scores and epithelial cell apoptosis. Abundance of TNF-α, IL-1ß, and IL6 mRNA were significantly decreased with each compound. In vitro and in vivo intestinal drug absorption, as well as measures of blood pressure and mucosal and colonic blood flow, showed significantly lower uptake of deschloro-losartan compared to losartan and candesartan. CONCLUSIONS: This study demonstrated efficacy of high-dose angiotensin II type Ia receptor antagonists in this colitis model. We postulate that a specially designed angiotensin II type Ia receptor antagonist with poor oral absorption may have great potential as a new therapeutic agent for inflammatory bowel disease in the future.


Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Bencimidazoles/farmacología , Colitis/inducido químicamente , Losartán/farmacología , Tetrazoles/farmacología , Administración Oral , Bloqueadores del Receptor Tipo 1 de Angiotensina II/administración & dosificación , Animales , Bencimidazoles/administración & dosificación , Bencimidazoles/química , Compuestos de Bifenilo , Colitis/tratamiento farmacológico , Colitis/patología , Colon/patología , Citocinas/genética , Citocinas/metabolismo , Sulfato de Dextran/toxicidad , Heces/química , Regulación de la Expresión Génica/efectos de los fármacos , Losartán/administración & dosificación , Losartán/análogos & derivados , Masculino , Ratones , Estructura Molecular , Organismos Libres de Patógenos Específicos , Tetrazoles/administración & dosificación , Tetrazoles/química
5.
Arch Pharm (Weinheim) ; 344(9): 617-26, 2011 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-21713967

RESUMEN

We recently reported a series of 1-acyl-N-(biphenyl-4-ylmethyl)pyrrolidine-2-carboxamides as AT(1) receptor ligands. The most potent compound of the series, 1-pentanoyl-N-{[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-pyrrolidine-2-carboxamide, showed an interesting affinity for the receptor. To investigate the influence of structure variations on affinity, the synthesis of additional compounds belonging to this series has been performed. Biological tests run on the newly synthesized compounds on CHO-hAT(1) cells stably expressing the human AT(1) receptor confirm our previous hypothesis, i.e. that, within this series, the length of the acyl chain, the substitution of the amidic group and the nature of the acidic one are crucial for the receptor interaction, being a valeric chain, a secondary amidic function and the tetrazole moiety, respectively, the optimal ones.


Asunto(s)
Antagonistas de Receptores de Angiotensina/química , Antagonistas de Receptores de Angiotensina/farmacología , Losartán/análogos & derivados , Pirrolidinas/química , Receptor de Angiotensina Tipo 1/metabolismo , Antagonistas de Receptores de Angiotensina/síntesis química , Animales , Compuestos de Bifenilo/química , Células CHO , Cricetinae , Humanos , Ligandos , Losartán/síntesis química , Losartán/química , Losartán/farmacología , Estructura Molecular , Unión Proteica , Pirrolidinas/síntesis química , Tetrazoles/química
6.
J Comput Aided Mol Des ; 24(9): 749-58, 2010 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-20623162

RESUMEN

A new 1,5 disubstituted imidazole AT(1) Angiotensin II (AII) receptor antagonist related to losartan with reversion of butyl and hydroxymethyl groups at the 2-, 5-positions of the imidazole ring was synthesized and evaluated for its antagonist activity (V8). In vitro results indicated that the reorientation of butyl and hydroxymethyl groups on the imidazole template of losartan retained high binding affinity to the AT(1) receptor concluding that the spacing of the substituents at the 2,5- positions is of primary importance. The docking studies are confirmed by binding assay results which clearly show a comparable binding score of the designed compound V8 with that of the prototype losartan. An efficient, regioselective and cost effective synthesis renders the new compound as an attractive candidate for advanced toxicological evaluation and a drug against hypertension.


Asunto(s)
Angiotensina II/antagonistas & inhibidores , Antagonistas de Receptores de Angiotensina , Diseño de Fármacos , Losartán/análogos & derivados , Antagonistas de Receptores de Angiotensina/síntesis química , Antagonistas de Receptores de Angiotensina/química , Antagonistas de Receptores de Angiotensina/farmacología , Animales , Antihipertensivos/síntesis química , Antihipertensivos/química , Humanos , Hipertensión/tratamiento farmacológico , Imidazoles/síntesis química , Receptores de Angiotensina/química , Receptores de Angiotensina/metabolismo , Receptores de Droga/química , Receptores de Droga/metabolismo , Relación Estructura-Actividad
7.
J Med Chem ; 63(21): 12213-12242, 2020 11 12.
Artículo en Inglés | MEDLINE | ID: mdl-32463237

RESUMEN

Pathogenic thrombus formation accounts for the etiology of many serious conditions including myocardial infarction, stroke, deep vein thrombosis, and pulmonary embolism. Despite the development of numerous anticoagulants and antiplatelet agents, the mortality rate associated with these diseases remains high. In recent years, however, significant epidemiological evidence and clinical models have emerged to suggest that modulation of the glycoprotein VI (GPVI) platelet receptor could be harnessed as a novel antiplatelet strategy. As such, many peptidic agents have been described in the past decade, while more recent efforts have focused on the development of small molecule modulators. Herein the rationale for targeting GPVI is summarized and the published GPVI modulators are reviewed, with particular focus on small molecules. A qualitative pharmacophore hypothesis for small molecule ligands at GPVI is also presented.


Asunto(s)
Inhibidores de Agregación Plaquetaria/uso terapéutico , Glicoproteínas de Membrana Plaquetaria/metabolismo , Trombosis/tratamiento farmacológico , Sitios de Unión , Productos Biológicos/química , Productos Biológicos/metabolismo , Humanos , Ligandos , Losartán/análogos & derivados , Losartán/metabolismo , Losartán/uso terapéutico , Simulación de Dinámica Molecular , Inhibidores de Agregación Plaquetaria/química , Inhibidores de Agregación Plaquetaria/farmacología , Glicoproteínas de Membrana Plaquetaria/química , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Transducción de Señal/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/metabolismo , Bibliotecas de Moléculas Pequeñas/farmacología , Bibliotecas de Moléculas Pequeñas/uso terapéutico , Trombosis/patología
8.
Arch Pharm Res ; 32(7): 1005-11, 2009 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-19641881

RESUMEN

HM70186, a medoxomil ester of EXP3174 which is an active metabolite of angiotensin II receptor blocker losartan, was synthesized, and its antihypertensive efficacy was evaluated in rats with hepatic dysfunction. Male Wistar rats were intraperitoneally injected with 0.5 mL/kg of carbon tetrachloride to cause hepatic injury, and implanted with an osmotic minipump containing angiotensin II (0.4 mg/kg/day) to induce hypertension. After confirmation of both hepatic damage and hypertension, the rats were orally administered losartan or HM70186, and then blood pressure and heart rate were monitored for 24 h. In normal animals, angiotensin II-induced hypertension was lowered by losartan, resulting in an ED(-30 mmHg) of 9.05 mg/kg. HM70186 also immediately decreased the blood pressure in a dose-dependent manner, exhibiting an ED(-30 mmHg) of 0.89 ng/kg (10,000 times the potency observed with losartan). Moreover, HM70186 (3 ng/kg) exerted a strong antihypertensive effect even in rats with hepatic injury, while losartan (10 microg/kg) was ineffective. These results suggest that HM70186 could be a promising candidate for the treatment of hypertension accompanied by hepatic dysfunction.


Asunto(s)
Antihipertensivos/farmacología , Presión Sanguínea/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Hepatopatías/fisiopatología , Losartán/análogos & derivados , Losartán/farmacología , Administración Oral , Angiotensina II , Animales , Antihipertensivos/administración & dosificación , Tetracloruro de Carbono , Enfermedad Hepática Inducida por Sustancias y Drogas , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Frecuencia Cardíaca/efectos de los fármacos , Hipertensión/inducido químicamente , Hipertensión/fisiopatología , Hepatopatías/patología , Losartán/administración & dosificación , Masculino , Ratas , Ratas Wistar , Factores de Tiempo
9.
Arterioscler Thromb Vasc Biol ; 27(5): 1184-90, 2007 May.
Artículo en Inglés | MEDLINE | ID: mdl-17347483

RESUMEN

OBJECTIVE: Thrombus formation after atherosclerotic plaque rupture critically involves the platelet collagen receptor glycoprotein (GP) VI. We investigated the impact of EXP3179, an active metabolite of the angiotensin II type 1 (AT1)-receptor antagonist Losartan (LOS) on GPVI-dependent platelet activation. METHODS AND RESULTS: EXP3179 and LOS but not EXP3174--the major AT1-receptor blocking metabolite of LOS--dose-dependently inhibited collagen-I (P<0.01) and GPVI-dependent platelet aggregation (P<0.01) analyzed by optical aggregometry. Platelet activation was further determined by flow cytometry measuring the expression of platelet PAC-1, an epitope of the activated fibrinogen-receptor complex. EXP3179 and LOS inhibited collagen-I (P<0.01) and GPVI-dependent PAC-1 expression (P<0.01). EXP3179 and LOS but not EXP3174 decreased the adhesion of GPVI-receptor expressing Chinese hamster ovarian cells on collagen-I under arterial shear conditions determined by flow chamber analysis (P<0.01 and P<0.05). EXP3179 also reduced human atherosclerotic plaque material-induced platelet aggregation (P<0.01) in vitro and murine platelet adhesion after acute vessel injury in vivo as determined by intravital microscopy (P<0.01). CONCLUSION: EXP3179 acts as a specific inhibitor of the platelet collagen receptor GPVI independent of AT1-receptor antagonism. Further investigations may clarify its individual potential as a novel pharmacological approach to specifically inhibit atherothrombotic events by GPVI-receptor blockade.


Asunto(s)
Aterosclerosis/complicaciones , Losartán/análogos & derivados , Agregación Plaquetaria/efectos de los fármacos , Glicoproteínas de Membrana Plaquetaria/metabolismo , Trombosis , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Aterosclerosis/sangre , Citometría de Flujo , Humanos , Losartán/uso terapéutico , Microscopía Fluorescente , Glicoproteínas de Membrana Plaquetaria/antagonistas & inhibidores , Receptor de Angiotensina Tipo 1/efectos de los fármacos , Trombosis/sangre , Trombosis/etiología , Trombosis/prevención & control , Resultado del Tratamiento
10.
Sci Rep ; 7: 41865, 2017 02 03.
Artículo en Inglés | MEDLINE | ID: mdl-28157237

RESUMEN

Excessive myocardial collagen deposition and cross-linking (CCL), a process regulated by lysyl oxidase (LOX), determines left ventricular (LV) stiffness and dysfunction. The angiotensin II antagonist losartan, metabolized to the EXP3179 and EXP3174 metabolites, reduces myocardial fibrosis and LV stiffness in hypertensive patients. Our aim was to investigate the differential influence of losartan metabolites on myocardial LOX and CCL in an experimental model of hypertension with myocardial fibrosis, and whether EXP3179 and EXP3174 modify LOX expression and activity in fibroblasts. In rats treated with NG-nitro-L-arginine methyl ester (L-NAME), administration of EXP3179 fully prevented LOX, CCL and connective tissue growth factor (CTGF) increase, as well as fibrosis, without normalization of blood pressure (BP). In contrast, administration of EXP3174 normalized BP and attenuated fibrosis but did not modify LOX, CCL and CTGF. In TGF-ß1-stimulated fibroblasts, EXP3179 inhibited CTGF and LOX expression and activity with lower IC50 values than EXP3174. Our results indicate that, despite a lower antihypertensive effect, EXP3179 shows higher anti-fibrotic efficacy than EXP3174, likely through its ability to prevent the excess of LOX and CCL. It is suggested that the anti-fibrotic effect of EXP3179 may be partially mediated by the blockade of CTGF-induced LOX in fibroblasts.


Asunto(s)
Antihipertensivos/farmacología , Losartán/análogos & derivados , Miocardio/metabolismo , Disfunción Ventricular Izquierda/tratamiento farmacológico , Animales , Antihipertensivos/farmacocinética , Antihipertensivos/uso terapéutico , Presión Sanguínea , Línea Celular , Factor de Crecimiento del Tejido Conjuntivo/metabolismo , Fibrosis , Humanos , Losartán/farmacocinética , Losartán/farmacología , Losartán/uso terapéutico , Masculino , Miocardio/citología , Miocardio/patología , Miofibroblastos/efectos de los fármacos , Miofibroblastos/metabolismo , Proteína-Lisina 6-Oxidasa/metabolismo , Ratas , Ratas Wistar , Factor de Crecimiento Transformador beta/farmacología , Disfunción Ventricular Izquierda/metabolismo
11.
Circ Res ; 90(7): 770-6, 2002 Apr 19.
Artículo en Inglés | MEDLINE | ID: mdl-11964369

RESUMEN

Angiotensin II (Ang II) type 1 receptor (AT(1)) antagonists such as losartan (LOS) are widely used for the treatment of hypertension and elicit antiinflammatory and antiaggregatory in vitro and in patients, although the underlying mechanism are unclear. Following computer-based molecule similarity, we proposed that on cytochrome-P450 degradation, the LOS metabolite EXP3179 is generated, which shows molecule homology to indomethacin, a cyclooxygenase inhibitor with antiinflammatory and antiaggregatory properties. Subsequently, serum-levels of EXP3179 were determined for 8 hours in patients receiving a single oral dose of 100 mg LOS. High-performance liquid chromatography followed by liquid chromatography-mass spectrometry (GC-MS) [corrected] from serum samples revealed a maximum of 10(-7) mol/L for EXP3179 peaking between 3 to 4 hours. The increase in serum-EXP3179 levels was associated with a significant reduction in platelet aggregation in vivo (-35+/-4%, P<0.001 versus control). EXP3179 generation was investigated in a chemical reaction mimicking the liver cytochrome-P450-dependent LOS-degradation and human endothelial cells were exposed to Ang II or lipopolysaccharides (LPS) in the presence of EXP3179 (10(-7) mol/L). LPS- and Ang II-induced COX-2 transcription was abolished by EXP3179. Moreover, EXP3179 significantly reduced Ang II- and LPS-induced formation of prostaglandin F2alpha as determined by GC-MS [corrected]. Thus, antiinflammatory properties of LOS are mediated via its EXP3179 metabolite by abolishing COX-2 mRNA upregulation and COX-dependent TXA2 and PGF2alpha generation. Serum levels of EXP3179 are detectable in patients in concentrations that exhibit antiinflammatory and antiaggregatory properties in vitro.


Asunto(s)
Antagonistas de Receptores de Angiotensina , Hipertensión/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Losartán/metabolismo , Losartán/farmacología , Agregación Plaquetaria/efectos de los fármacos , Angiotensina II/farmacología , Ácido Araquidónico/farmacología , Biotransformación , Células Cultivadas , Ciclooxigenasa 2 , Dinoprost/antagonistas & inhibidores , Dinoprost/biosíntesis , Diseño de Fármacos , Endotelio Vascular/citología , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Activación Enzimática/efectos de los fármacos , Femenino , Humanos , Hipertensión/metabolismo , Imidazoles/sangre , Inflamación/metabolismo , Molécula 1 de Adhesión Intercelular/genética , Molécula 1 de Adhesión Intercelular/metabolismo , Isoenzimas/antagonistas & inhibidores , Isoenzimas/genética , Isoenzimas/metabolismo , Lipopolisacáridos/farmacología , Losartán/análogos & derivados , Losartán/química , Masculino , Proteínas de la Membrana , Persona de Mediana Edad , Prostaglandina-Endoperóxido Sintasas/genética , Prostaglandina-Endoperóxido Sintasas/metabolismo , ARN Mensajero/análisis , ARN Mensajero/metabolismo , Receptor de Angiotensina Tipo 1 , Receptores de Angiotensina/metabolismo , Tetrazoles/sangre , Tromboxano A2/antagonistas & inhibidores , Tromboxano A2/biosíntesis , Regulación hacia Arriba/efectos de los fármacos , Vasoconstrictores/farmacología
12.
J Pharm Biomed Anal ; 40(5): 1097-104, 2006 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-16260110

RESUMEN

AT(1) antagonists constitute the most recent class of antihypertensive drugs which act through the Renin Angiotensin System (RAS). In an effort to comprehend their stereoelectronic features, a study was initiated to compare the conformational properties of drugs already marketed for the treatment of hypertension with synthetic ones, possessing common structural characteristics. In this study, the synthetic AT(1) antagonist V8 is structurally elucidated and its conformational properties are studied through a combination of NMR spectroscopy and computational analysis. Its conformational properties are compared with those of the structurally similar prototype AT(1) antagonist losartan.


Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/química , Losartán/análogos & derivados , Bloqueadores del Receptor Tipo 1 de Angiotensina II/análisis , Compuestos de Bifenilo/química , Dimetilsulfóxido , Imidazoles/química , Losartán/análisis , Losartán/química , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Conformación Molecular , Método de Montecarlo , Tetrazoles/química
13.
Curr Top Med Chem ; 4(4): 385-401, 2004.
Artículo en Inglés | MEDLINE | ID: mdl-14965308

RESUMEN

Peptidomimitism is applied to the medicinal chemistry in order to synthesize drugs that devoid of the disadvantages of peptides. AT1 antagonists constitute a new generation of drugs for the treatment of hypertension designed and synthesized to mimic the C-terminal segment of Angiotensin II and to block its binding action on AT1 receptor. An effort was made to understand the molecular basis of hypertension by studying the conformational analysis of Ang II and its derivatives as well as the AT1 antagonists belonging to SARTANs class of molecules. Such studies offer the possibility to reveal the stereoelectronic factors responsible for bioactivity of AT1 antagonists and to design and synthesize new analogs. An example will be given which proves that drugs with better pharmacological and financial profiles may arise based on this rational design.


Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II , Angiotensina II/análogos & derivados , Antihipertensivos/química , Diseño de Fármacos , 1-Sarcosina-8-Isoleucina Angiotensina II/análogos & derivados , 1-Sarcosina-8-Isoleucina Angiotensina II/química , Angiotensina II/química , Angiotensina II/farmacología , Antihipertensivos/síntesis química , Antihipertensivos/farmacología , Humanos , Hipertensión/tratamiento farmacológico , Losartán/análogos & derivados , Losartán/química , Espectroscopía de Resonancia Magnética , Conformación Molecular , Imitación Molecular , Péptidos/química , Péptidos/farmacología , Relación Estructura-Actividad
14.
J Hypertens ; 17(7): 873-81, 1999 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-10419059

RESUMEN

Angiotensin II (Ang II) acts at the cellular level on two receptor subtypes: the AT1 receptor which can be blocked by losartan and its analogues (the 'sartan family'), and the AT2 receptor that does not react with the above antagonists but which can be blocked by different compounds, such as PD123319. AT1 receptor blockade has proven to be a highly effective means of interference with the renin-angiotensin system (RAS) and hence of reducing high blood pressure. As a result of the terminal blockade of the RAS cascade, circulating Ang II levels tend to rise two- to threefold. The free access of such enhanced levels to uninhibited AT2 receptors may be clinically relevant, as argued in the present review. The most extensive experimental and clinical experience with AT1 receptor blockade so far has been obtained with the pioneer drug losartan, although major contributions have also been made on candesartan cilexetil, irbesartan and valsartan. All of these four drugs have been instrumental in substantial clinical trials, serving as sources of information in the clinically oriented part of this review. AT1 receptor blocking drugs generally provide a relatively gradual decrease in blood pressure, which is comparable to that obtained with conventional anti-hypertensive drugs. Clinical trials reveal an astounding lack of drug-related adverse effects, scoring even better than placebo in terms of frequencies and sometimes patterns. The trough/peak ratio on single dosages seems to have been mastered, particularly with the second generation of AT1 receptor blockers, as is evident from 24 h ambulatory blood pressure monitoring. Combination with low-dose thiazide regimens is well established. Intermediate endpoints (micro-albuminuria and left ventricular hypertrophy) appear to be controllable. Morbid cardiovascular sequelae are currently under study in comparison with beta- and calcium channel blockade.


Asunto(s)
Angiotensina II/metabolismo , Antagonistas de Receptores de Angiotensina , Antihipertensivos/uso terapéutico , Hipertensión/tratamiento farmacológico , Losartán/uso terapéutico , Humanos , Hipertensión/metabolismo , Hipertensión/fisiopatología , Losartán/análogos & derivados
15.
J Med Chem ; 47(23): 5597-600, 2004 Nov 04.
Artículo en Inglés | MEDLINE | ID: mdl-15509155

RESUMEN

The aim of this work was to develop lead pharmacodynamic hybrids, NO-sartans, possessing the characteristics of a typical AT1-antagonist and of a "slow NO donor", by adding NO-donor side chains to losartan. These new compounds, 2a and 2b, displayed vasorelaxing effects, due to the release of NO, and antagonized the vasocontractile effects of angiotensin II, with potency values similar to that of losartan. In vivo, the antihypertensive effects of 2a were similar to those of losartan and captopril.


Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/síntesis química , Antihipertensivos/síntesis química , Losartán/análogos & derivados , Losartán/síntesis química , Vasodilatadores/síntesis química , Bloqueadores del Receptor Tipo 1 de Angiotensina II/química , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Animales , Antihipertensivos/farmacología , Presión Sanguínea/efectos de los fármacos , Losartán/farmacología , Ratas , Ratas Endogámicas SHR , Relación Estructura-Actividad , Vasodilatadores/farmacología
16.
J Pharm Biomed Anal ; 31(5): 833-44, 2003 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-12684096

RESUMEN

One of the major systems which interferes with the disease of hypertension, is the Renin Angiotensin Aldosterone System (RAS). The octapeptide hormone angiotensin II is the active product of RAS which causes vasoconstriction when binds to the AT(1) receptor. In the last years, there has been a development of drugs which block the Angiotensin II from binding the AT(1) receptor and are called AT(1) antagonists. In an effort to comprehend their stereoelectronic features, a study has been initiated to compare the conformational properties of drugs already marketed for the treatment of hypertension and others which are designed and synthesized in our laboratory possessing structural characteristics necessary for antihypertensive activity. In this study, two synthetic non-peptide AT(1) antagonists, are structurally elucidated and their conformational properties and bioactivity are compared to the prototype and first approved drug of this category in the market; losartan (trade name: COZAAR).


Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II , Angiotensina II/metabolismo , Antihipertensivos/farmacología , Compuestos de Bencilo/farmacología , Losartán/farmacología , Animales , Antihipertensivos/química , Compuestos de Bencilo/química , Presión Sanguínea/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Losartán/análogos & derivados , Losartán/química , Espectroscopía de Resonancia Magnética , Masculino , Modelos Moleculares , Conformación Molecular , Conejos , Receptor de Angiotensina Tipo 1/química
17.
Artículo en Inglés | MEDLINE | ID: mdl-22770781

RESUMEN

A simple and rapid quantitative bioanalytical liquid chromatography-tandem mass spectrometric (LC-MS/MS) method for simultaneous determination of losartan and its active metabolite, losartan carboxylic acid on rat dried blood spots was developed and validated as per regulatory guidelines. Losartan and its metabolite were extracted from dried blood spots using 50% aqueous methanol and separated on Waters XTerra(®) RP18 (250 mm × 4.6 mm, 5 µm) column using mobile phase composed of 40% acetonitrile and 60% aqueous ammonium acetate (10mM). The eluents were monitored using ESI tandem mass spectrometric detection with negative polarity in MRM mode using ion transitions m/z 421.2→179.0, m/z 435.3→157.0 and m/z 427.3→193.0 for losartan, losartan carboxylic acid and Irbesartan (internal standard), respectively. The method was validated over the linear range of 1-200 ng/mL and 5-1000 ng/mL with lower limits of quantification of 1.0 ng/mL and 5.0 ng/mL for losartan and losartan carboxylic acid, respectively. Inter and intra-day precision and accuracy (Bias) were below 5.96% and between -2.8 and 1.5%, respectively. The mean recoveries of the analytes from dried blood spots were between 89% and 97%. No significant carry over and matrix effects were observed. The stability of stock solution, whole blood, dried blood spot and processed samples were tested under different conditions and the results were found to be well within the acceptable limits. Additional validation parameters such as influence of hematocrit and spot volume were also evaluated and found to be well within the acceptable limits.


Asunto(s)
Cromatografía Liquida/métodos , Pruebas con Sangre Seca/métodos , Losartán/sangre , Espectrometría de Masas en Tándem/métodos , Animales , Estabilidad de Medicamentos , Modelos Lineales , Losartán/análogos & derivados , Losartán/química , Losartán/metabolismo , Metanol , Ratas , Reproducibilidad de los Resultados , Sensibilidad y Especificidad
19.
Hypertension ; 54(4): 738-43, 2009 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-19687349

RESUMEN

The losartan metabolite EXP3174 exhibits angiotensin II receptor 1 (AT1R)-blocking properties, whereas the metabolite EXP3179 potently induces the activity of the insulin-sensitizing peroxisome proliferator-activated receptor gamma (PPARgamma) as a partial agonist in vitro. We investigated whether chronic treatment with losartan leads to sufficient serum levels of EXP3179 to activate PPARgamma in monocytes derived from losartan-treated patients. Hypertensive patients (n=15) treated with losartan (100 mg/daily for at least the past 2 months) and untreated control patients (n=7) were included. Monocytes were extracted by negative isolation using a Dynal Monocyte Kit, followed by analysis of PPARgamma target gene expression (CD36, ABC transporter G1 [ABCG1]) by quantitative real-time RT-PCR. Serum was prepared before, 2, 4, and 6 hours after losartan (100 mg) ingestion for HPLC-based determination of losartan, EXP3174, and EXP3179. Chronic treatment with losartan resulted in basal levels of losartan, EXP3174, and EXP3179 of 348.3+/-101.8 ng/mL, 115.3+/-56.1 ng/mL, and 176.2+/-143.4 ng/mL, respectively. Levels of both EXP3174 and EXP3179 were time-dependently increased in serum with a maximum 2 hours after drug intake (1706.0+/-760.1 ng/mL, 808.9+/-618.2 ng/mL, respectively). In consonance with detectable PPARgamma-activating EXP3179 serum levels, monocytic PPARgamma target gene expression was significantly upregulated in patients treated with losartan by 3.75+/-0.95- and 252.02+/-46.86-fold for CD36 and ABCG1 (P=0.043, P=0.0045 versus control patients, respectively). This is the first clinical description of monocytic PPARgamma-target gene regulation by chronic treatment with losartan, which likely is mediated by its metabolite EXP3179. Our data show that sufficient serum levels of EXP3179 are present under losartan treatment. PPARgamma activation by AT1R-blockers may translate into synergistic beneficial actions in monocytes.


Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Hipertensión/tratamiento farmacológico , Hipertensión/metabolismo , Losartán/análogos & derivados , Losartán/uso terapéutico , PPAR gamma/metabolismo , Anciano , Bloqueadores del Receptor Tipo 1 de Angiotensina II/sangre , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Bencimidazoles/farmacología , Benzoatos/farmacología , Compuestos de Bifenilo/farmacología , Movimiento Celular , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Hipertensión/patología , Imidazoles/farmacocinética , Imidazoles/farmacología , Irbesartán , Losartán/sangre , Losartán/farmacocinética , Losartán/farmacología , Masculino , Persona de Mediana Edad , Células Musculares/efectos de los fármacos , Células Musculares/metabolismo , Células Musculares/patología , PPAR gamma/agonistas , Telmisartán , Tetrazoles/farmacocinética , Tetrazoles/farmacología
20.
Hypertension ; 54(4): 744-50, 2009 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-19687351

RESUMEN

Oxidative stress plays a critical role in the pathogenesis of hypertension. The NADPH oxidase constitutes a major source of superoxide anion in phagocytic cells, and its activation is associated with matrix metalloproteinase (MMP)-9 secretion by these cells. We investigated the effects of the angiotensin II type 1 receptor antagonist losartan and its metabolites (EXP3174 and EXP3179) on NADPH oxidase activity and MMP-9 secretion in human phagocytic cells. EXP3179, but not losartan and EXP3174, dose-dependently inhibited (P<0.05) phorbol myristate acetate and insulin-stimulated NADPH oxidase activity. EXP3179 also inhibited phorbol myristate acetate-induced NADPH oxidase in endothelial cells. In addition, EXP3179 inhibited (P<0.05) both phorbol myristate acetate-stimulated p47phox translocation from cytosol to membranes and protein kinase C activity. Affinity experiments and enzymatic assays confirmed that EXP3179 inhibited several protein kinase C isoforms. EXP3179 also inhibited (P<0.05) phorbol myristate acetate-stimulated MMP-9 secretion. In a study performed in 153 hypertensive patients, phagocytic NADPH oxidase activity was lower (P<0.05) in losartan-treated compared with untreated patients and in patients treated with other angiotensin II type 1 receptor antagonists or with angiotensin-converting enzyme inhibitors. Plasma levels of MMP-9 were lower (P<0.05) in losartan-treated hypertensives compared with the other group of patients. Thus, EXP3179 acts as a blocker of the NADPH oxidase in phagocytic cells by a potential mechanism that targets the protein kinase C signaling pathway. This effect can be involved in reduced MMP-9 secretion by these cells. It is proposed that the EXP3179 metabolite may confer to losartan the specific capacity to reduce oxidative stress mediated by phagocytic cells in hypertensive patients.


Asunto(s)
Hipertensión/tratamiento farmacológico , Hipertensión/metabolismo , Losartán/análogos & derivados , Losartán/metabolismo , Losartán/uso terapéutico , NADPH Oxidasas/antagonistas & inhibidores , Proteína Quinasa C/antagonistas & inhibidores , Superóxidos/metabolismo , Anciano , Bloqueadores del Receptor Tipo 1 de Angiotensina II/metabolismo , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Femenino , Humanos , Hipertensión/patología , Imidazoles/metabolismo , Imidazoles/farmacología , Losartán/farmacología , Masculino , Metaloproteinasa 9 de la Matriz/metabolismo , Persona de Mediana Edad , NADPH Oxidasas/metabolismo , Estrés Oxidativo/fisiología , Oxígeno/metabolismo , Fagocitos/efectos de los fármacos , Fagocitos/metabolismo , Fagocitos/patología , Proteína Quinasa C/metabolismo , Transducción de Señal/fisiología , Tetrazoles/metabolismo , Tetrazoles/farmacología
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