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1.
Toxicol Appl Pharmacol ; 394: 114961, 2020 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-32209365

RESUMEN

INTRODUCTION: hERG block potency is widely used to calculate a drug's safety margin against its torsadogenic potential. Previous studies are confounded by use of different patch clamp electrophysiology protocols and a lack of statistical quantification of experimental variability. Since the new cardiac safety paradigm being discussed by the International Council for Harmonisation promotes a tighter integration of nonclinical and clinical data for torsadogenic risk assessment, a more systematic approach to estimate the hERG block potency and safety margin is needed. METHODS: A cross-industry study was performed to collect hERG data on 28 drugs with known torsadogenic risk using a standardized experimental protocol. A Bayesian hierarchical modeling (BHM) approach was used to assess the hERG block potency of these drugs by quantifying both the inter-site and intra-site variability. A modeling and simulation study was also done to evaluate protocol-dependent changes in hERG potency estimates. RESULTS: A systematic approach to estimate hERG block potency is established. The impact of choosing a safety margin threshold on torsadogenic risk evaluation is explored based on the posterior distributions of hERG potency estimated by this method. The modeling and simulation results suggest any potency estimate is specific to the protocol used. DISCUSSION: This methodology can estimate hERG block potency specific to a given voltage protocol. The relationship between safety margin thresholds and torsadogenic risk predictivity suggests the threshold should be tailored to each specific context of use, and safety margin evaluation may need to be integrated with other information to form a more comprehensive risk assessment.


Asunto(s)
Canal de Potasio ERG1/antagonistas & inhibidores , Medición de Riesgo/métodos , Torsades de Pointes/inducido químicamente , Teorema de Bayes , Simulación por Computador , Humanos , Modelos Biológicos , Técnicas de Placa-Clamp , Bloqueadores de los Canales de Potasio/farmacología , Seguridad , Torsades de Pointes/fisiopatología
2.
Toxicol Appl Pharmacol ; 329: 121-127, 2017 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-28546047

RESUMEN

Current in vitro approaches to cardiac safety testing typically focus on mechanistic ion channel testing to predict in vivo proarrhythmic potential. Outside of the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative, structural and functional cardiotoxicity related to chronic dosing effects are of great concern as these effects can impact compound attrition. Development and implementation of an in vitro cardiotoxicity screening platform that effectively identifies these liabilities early in the discovery process should reduce costly attrition and decrease preclinical development time. Impedence platforms have the potential to accurately identify structural and functional cardiotoxicity and have sufficient throughput to be included in a multi-parametric optimization approach. Human induced pluripotent stem cell cardiomyocytes (hIPSC-CMs) have demonstrated utility in cardiac safety and toxicity screening. The work described here leverages these advantages to assess the predictive value of data generated by two impedance platforms. The response of hIPSC-CMs to compounds with known or predicted cardiac functional or structural toxicity was determined. The compounds elicited cardiac activities and/or effects on "macro" impedance often associated with overt structural or cellular toxicity, detachment, or hypertrophy. These assays correctly predicted in vivo cardiotox findings for 81% of the compounds tested and did not identify false positives. In addition, internal or literature Cmax values from in vivo studies correlated within 4 fold of the in vitro observations. The work presented here demonstrates the predictive power of impedance platforms with hIPSC-CMs and provides a means toward accelerating lead candidate selection by assessing preclinical cardiac safety earlier in the drug discovery process.


Asunto(s)
Arritmias Cardíacas/inducido químicamente , Bioensayo , Descubrimiento de Drogas/métodos , Células Madre Pluripotentes Inducidas/efectos de los fármacos , Miocitos Cardíacos/efectos de los fármacos , Pruebas de Toxicidad/métodos , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/patología , Arritmias Cardíacas/fisiopatología , Cardiotoxicidad , Diferenciación Celular , Linaje de la Célula , Células Cultivadas , Relación Dosis-Respuesta a Droga , Impedancia Eléctrica , Frecuencia Cardíaca/efectos de los fármacos , Ensayos Analíticos de Alto Rendimiento , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Células Madre Pluripotentes Inducidas/patología , Estructura Molecular , Contracción Miocárdica/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Fenotipo , Reproducibilidad de los Resultados , Medición de Riesgo , Relación Estructura-Actividad , Factores de Tiempo
4.
J Med Chem ; 64(20): 15214-15249, 2021 10 28.
Artículo en Inglés | MEDLINE | ID: mdl-34614347

RESUMEN

Novel bacterial topoisomerase inhibitors (NBTIs) are among the most promising new antibiotics in preclinical/clinical development. We previously reported dioxane-linked NBTIs with potent antistaphylococcal activity and reduced hERG inhibition, a key safety liability. Herein, polarity-focused optimization enabled the delineation of clear structure-property relationships for both microsomal metabolic stability and hERG inhibition, resulting in the identification of lead compound 79. This molecule demonstrates potent antibacterial activity against diverse Gram-positive pathogens, inhibition of both DNA gyrase and topoisomerase IV, a low frequency of resistance, a favorable in vitro cardiovascular safety profile, and in vivo efficacy in a murine model of methicillin-resistant Staphylococcus aureus infection.


Asunto(s)
Antibacterianos/farmacología , Dioxanos/farmacología , Inhibidores Enzimáticos/farmacología , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Antibacterianos/síntesis química , Antibacterianos/química , Girasa de ADN/metabolismo , Topoisomerasa de ADN IV/antagonistas & inhibidores , Topoisomerasa de ADN IV/metabolismo , Dioxanos/síntesis química , Dioxanos/química , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Canales de Potasio Éter-A-Go-Go/metabolismo , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Relación Estructura-Actividad
5.
Microorganisms ; 9(3)2021 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-33801811

RESUMEN

Outbreaks of Ebola ebolavirus (EBOV) have been associated with high morbidity and mortality. Milestones have been reached recently in the management of EBOV disease (EVD) with licensure of an EBOV vaccine and two monoclonal antibody therapies. However, neither vaccines nor therapies are available for other disease-causing filoviruses. In preparation for such outbreaks, and for more facile and cost-effective management of EVD, we seek a cocktail containing orally available and room temperature stable drugs with strong activity against multiple filoviruses. We previously showed that (bepridil + sertraline) and (sertraline + toremifene) synergistically suppress EBOV in cell cultures. Here, we describe steps towards testing these combinations in a mouse model of EVD. We identified a vehicle suitable for oral delivery of the component drugs and determined that, thus formulated the drugs are equally active against EBOV as preparations in DMSO, and they maintain activity upon storage in solution for up to seven days. Pharmacokinetic (PK) studies indicated that the drugs in the oral delivery vehicle are well tolerated in mice at the highest doses tested. Collectively the data support advancement of these combinations to tests for synergy in a mouse model of EVD. Moreover, mathematical modeling based on human oral PK projects that the combinations would be more active in humans than their component single drugs.

6.
Eur J Med Chem ; 199: 112324, 2020 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-32402932

RESUMEN

A series of Novel Bacterial Topoisomerase Inhibitors (NBTIs) employing a linker derived from isomannide were synthesized and evaluated. Reduced hERG inhibition was observed compared to structure-matched analogues with different linkers, and compound 6 showed minimal proarrhythmic potential using an in vitro panel of cardiac ion channels. Compound 6 also displayed excellent activity against fluoroquinolone-resistant MRSA (MIC90 = 2 µg/mL) and other Gram-positive pathogens.


Asunto(s)
Antibacterianos/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Bacterias Grampositivas/efectos de los fármacos , Inhibidores de Topoisomerasa/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Relación Dosis-Respuesta a Droga , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Relación Estructura-Actividad , Inhibidores de Topoisomerasa/síntesis química , Inhibidores de Topoisomerasa/química
7.
Circulation ; 105(6): 759-65, 2002 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-11839634

RESUMEN

BACKGROUND: Therapeutic angiogenesis is a new approach to treating ischemic heart disease, and the optimal method for assessing its efficacy is unclear. We used myocardial contrast echocardiography (MCE) to evaluate the therapeutic response to the angiogenic agent, vascular endothelial growth factor-121 (VEGF121). METHODS AND RESULTS: After placement of an ameroid constrictor (day 0) around the left anterior descending artery (LAD), dogs were given intracoronary VEGF121 protein (108 microg, n=6) or placebo (n=6) on days 7 and 21, and subcutaneous VEGF121 (1 mg) or placebo on days 8 to 20 and 22 to 27. On day 48, MCE was performed during rest and dobutamine stress. Videointensity (y) and pulsing interval (t) were fit to an exponential model (y=A[1-e(-beta(t))]) used to derive indices of red cell velocity (beta) and capillary area (A), and parameters were compared with radiolabeled microsphere flow data. VEGF(121) treatment resulted in higher resting left anterior descending artery/left circumflex flow ratio compared with placebo (P<0.03) and improved collateral flow reserve. Beta was 0.94+/-0.37 in VEGF121 dogs versus 0.38+/-0.31 in controls (P<0.02), with the greatest difference in the endocardium. The parameter A was comparable in both groups, suggesting that microvascular changes did not alter capillary cross-sectional area, and histology indicated a trend toward higher arteriolar density in VEGF121-treated animals. CONCLUSIONS: VEGF121 protein improves collateral flow and reserve. MCE can evaluate the transmural location and structural and functional responses of the microvasculature to angiogenic interventions.


Asunto(s)
Enfermedad Coronaria/diagnóstico por imagen , Enfermedad Coronaria/tratamiento farmacológico , Ecocardiografía , Factores de Crecimiento Endotelial/farmacología , Linfocinas/farmacología , Microcirculación/efectos de los fármacos , Microcirculación/diagnóstico por imagen , Animales , Velocidad del Flujo Sanguíneo/efectos de los fármacos , Circulación Colateral/efectos de los fármacos , Circulación Coronaria/efectos de los fármacos , Modelos Animales de Enfermedad , Perros , Electrocardiografía , Corazón/efectos de los fármacos , Revascularización Miocárdica , Miocardio/patología , Valor Predictivo de las Pruebas , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial Vascular
8.
Mol Pharmacol ; 68(3): 876-84, 2005 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-15976038

RESUMEN

A variety of drugs has been reported to cause acquired long QT syndrome through inhibition of the IKr channel. Screening compounds in early discovery and development stages against their ability to inhibit IKr or the hERG channel has therefore become an indispensable procedure in the pharmaceutical industry. In contrast to numerous hERG channel blockers discovered during screening, only (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)-3-oxo-propyl]-1-[3-(2,3,5-trifluoro-phenyl)-prop-2-ynyl]-piperidine-3-carboxylic acid (RPR260243) has been reported so far to enhance the hERG current. In this article, we describe several potent mechanistically distinct hERG channel enhancers. One example is PD-118057 (2-{4-[2-(3,4-dichloro-phenyl)-ethyl]-phenylamino}-benzoic acid) which produced average increases of 5.5 +/- 1.1, 44.8 +/- 3.1, and 111.1 +/- 21.7% in the peak tail hERG current at 1, 3, and 10 muM, respectively, in human embryonic kidney 293 cells. PD-118057 did not affect the voltage dependence and kinetics of gating parameters, nor did it require open conformation of the channel. In isolated guinea pig cardiomyocytes, PD-118057 showed no major effect on I(Na), I(Ca,L), I(K1), and I(Ks). PD-118057 shortened the action potential duration and QT interval in arterially perfused rabbit ventricular wedge preparation in a concentration-dependent manner. The presence of 3 muM PD-118057 prevented action potential duration and QT prolongation caused by dofetilide. "Early after-depolarizations" induced by dofetilide were also completely eliminated by 3 microM PD-118057. Although further investigation is warranted to evaluate the therapeutic value and safety profile of these compounds, our data support the notion that hERG activation by pharmaceuticals may offer a new approach in the treatment of delayed repolarization conditions, which may occur in patients with inherited or acquired long QT syndrome, congestive heart failure, and diabetes.


Asunto(s)
Antiarrítmicos/farmacología , Piperidinas/farmacología , Canales de Potasio con Entrada de Voltaje/agonistas , Quinolinas/farmacología , ortoaminobenzoatos/farmacología , Animales , Células Cultivadas , Clorobencenos , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go , Cobayas , Corazón/efectos de los fármacos , Humanos , Masculino , Fenetilaminas/farmacología , Canales de Potasio con Entrada de Voltaje/antagonistas & inhibidores , Canales de Potasio con Entrada de Voltaje/fisiología , Sulfonamidas/farmacología
9.
J Pharmacol Exp Ther ; 302(1): 320-7, 2002 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-12065733

RESUMEN

Several macrolides have been reported to cause QT prolongation and ventricular arrhythmias such as torsades de pointes. To clarify the underlying ionic mechanisms, we examined the effects of six macrolides on the human ether-a-go-go-related gene (HERG)-encoded potassium current stably expressed in human embryonic kidney-293 cells. All six drugs showed a concentration-dependent inhibition of the current with the following IC(50) values: clarithromycin, 32.9 microM; roxithromycin, 36.5 microM; erythromycin, 72.2 microM; josamycin, 102.4 microM; erythromycylamine, 273.9 microM; and oleandomycin, 339.6 microM. A metabolite of erythromycin, des-methyl erythromycin, was also found to inhibit HERG current with an IC(50) of 147.1 microM. These findings imply that the blockade of HERG may be a common feature of macrolides and may contribute to the QT prolongation observed clinically with some of these compounds. Mechanistic studies showed that inhibition of HERG current by clarithromycin did not require activation of the channel and was both voltage- and time-dependent. The blocking time course could be described by a first-order reaction between the drug and the channel. Both binding and unbinding processes appeared to speed up as the membrane was more depolarized, indicating that the drug-channel interaction may be affected by electrostatic responses.


Asunto(s)
Antibacterianos/farmacología , Proteínas de Transporte de Catión , Proteínas de Unión al ADN , Bloqueadores de los Canales de Potasio , Canales de Potasio con Entrada de Voltaje , Canales de Potasio , Transactivadores , Línea Celular , Claritromicina/farmacología , Canal de Potasio ERG1 , Electrofisiología , Canales de Potasio Éter-A-Go-Go , Humanos , Cinética , Síndrome de QT Prolongado/inducido químicamente , Potenciales de la Membrana/efectos de los fármacos , Técnicas de Placa-Clamp , Regulador Transcripcional ERG
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