Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 8 de 8
Filtrar
1.
J Pharmacol Exp Ther ; 367(1): 108-118, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-30076264

RESUMEN

Ocular neovascular diseases like wet age-related macular degeneration are a major cause of blindness. Novel therapies are greatly needed for these diseases. One appealing antiangiogenic target is reduction-oxidation factor 1-apurinic/apyrimidinic endonuclease 1 (Ref-1/APE1). This protein can act as a redox-sensitive transcriptional activator for nuclear factor (NF)-κB and other proangiogenic transcription factors. An existing inhibitor of Ref-1's function, APX3330, previously showed antiangiogenic effects. Here, we developed improved APX3330 derivatives and assessed their antiangiogenic activity. We synthesized APX2009 and APX2014 and demonstrated enhanced inhibition of Ref-1 function in a DNA-binding assay compared with APX3330. Both compounds were antiproliferative against human retinal microvascular endothelial cells (HRECs; GI50 APX2009: 1.1 µM, APX2014: 110 nM) and macaque choroidal endothelial cells (Rf/6a; GI50 APX2009: 26 µM, APX2014: 5.0 µM). Both compounds significantly reduced the ability of HRECs and Rf/6a cells to form tubes at mid-nanomolar concentrations compared with control, and both significantly inhibited HREC and Rf/6a cell migration in a scratch wound assay, reducing NF-κB activation and downstream targets. Ex vivo, APX2009 and APX2014 inhibited choroidal sprouting at low micromolar and high nanomolar concentrations, respectively. In the laser-induced choroidal neovascularization mouse model, intraperitoneal APX2009 treatment significantly decreased lesion volume by 4-fold compared with vehicle (P < 0.0001, ANOVA with Dunnett's post-hoc tests), without obvious intraocular or systemic toxicity. Thus, Ref-1 inhibition with APX2009 and APX2014 blocks ocular angiogenesis in vitro and ex vivo, and APX2009 is an effective systemic therapy for choroidal neovascularization in vivo, establishing Ref-1 inhibition as a promising therapeutic approach for ocular neovascularization.


Asunto(s)
ADN-(Sitio Apurínico o Apirimidínico) Liasa/metabolismo , Neovascularización Patológica/tratamiento farmacológico , Retina/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/farmacología , Animales , Línea Celular , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Femenino , Humanos , Macaca , Ratones , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Neovascularización Patológica/metabolismo , Retina/metabolismo
2.
J Pharmacol Exp Ther ; 359(2): 300-309, 2016 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-27608656

RESUMEN

Chemotherapy-induced peripheral neuropathy (CIPN) is a potentially debilitating side effect of a number of chemotherapeutic agents. There are currently no U.S. Food and Drug Administration-approved interventions or prevention strategies for CIPN. Although the cellular mechanisms mediating CIPN remain to be determined, several lines of evidence support the notion that DNA damage caused by anticancer therapies could contribute to the neuropathy. DNA damage in sensory neurons after chemotherapy correlates with symptoms of CIPN. Augmenting apurinic/apyrimidinic endonuclease (APE)-1 function in the base excision repair pathway reverses this damage and the neurotoxicity caused by anticancer therapies. This neuronal protection is accomplished by either overexpressing APE1 or by using a first-generation targeted APE1 small molecule, E3330 [(2E)-2-[(4,5-dimethoxy-2-methyl-3,6-dioxo-1,4-cyclohexadien-1-yl)methylene]-undecanoic acid; also called APX3330]. Although E3330 has been approved for phase 1 clinical trials (Investigational New Drug application number IND125360), we synthesized novel, second-generation APE1-targeted molecules and determined whether they would be protective against neurotoxicity induced by cisplatin or oxaliplatin while not diminishing the platins' antitumor effect. We measured various endpoints of neurotoxicity using our ex vivo model of sensory neurons in culture, and we determined that APX2009 [(2E)-2-[(3-methoxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)methylidene]-N,N-diethylpentanamide] is an effective small molecule that is neuroprotective against cisplatin and oxaliplatin-induced toxicity. APX2009 also demonstrated a strong tumor cell killing effect in tumor cells and the enhanced tumor cell killing was further substantiated in a more robust three-dimensional pancreatic tumor model. Together, these data suggest that the second-generation compound APX2009 is effective in preventing or reversing platinum-induced CIPN while not affecting the anticancer activity of platins.


Asunto(s)
Antineoplásicos/efectos adversos , ADN-(Sitio Apurínico o Apirimidínico) Liasa/metabolismo , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/prevención & control , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Cisplatino/efectos adversos , Sistema Enzimático del Citocromo P-450/metabolismo , Daño del ADN , Evaluación Preclínica de Medicamentos , Humanos , Modelos Moleculares , Conformación Molecular , Compuestos Organoplatinos/efectos adversos , Oxaliplatino , Enfermedades del Sistema Nervioso Periférico/enzimología , Células Receptoras Sensoriales/efectos de los fármacos , Células Receptoras Sensoriales/patología
3.
J Med Chem ; 47(22): 5367-80, 2004 Oct 21.
Artículo en Inglés | MEDLINE | ID: mdl-15481975

RESUMEN

Two closely related diaryl acylsulfonamides were recently reported as potent antitumor agents against a broad spectrum of human tumor xenografts (colon, lung, breast, ovary, and prostate) in nude mice. Especially intriguing was their activity against colorectal cancer xenografts. In this paper, rapid parallel synthesis along with traditional medicinal chemistry techniques were used to quickly delineate the structure-activity relationships of the substitution patterns in both phenyl rings of the acylsufonamide anti-proliferative scaffold. Although the molecular target of the compounds remains unclear, we determined that the vascular endothelial growth factor-dependent human umbilical vein endothelial cells assay in combination with a soft agar disk diffusion assay allowed for optimization of potency in the series. The pharmacokinetic properties and in vivo activity in an HCT116 xenograft model are reported for representative compounds.


Asunto(s)
Antineoplásicos/síntesis química , Sulfonamidas/síntesis química , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , División Celular/efectos de los fármacos , Línea Celular , Ensayos de Selección de Medicamentos Antitumorales , Endotelio Vascular/citología , Endotelio Vascular/efectos de los fármacos , Femenino , Semivida , Humanos , Técnicas In Vitro , Ratones , Ratones Desnudos , Relación Estructura-Actividad Cuantitativa , Ratas , Ratas Endogámicas F344 , Sulfonamidas/química , Sulfonamidas/farmacología , Trasplante Heterólogo , Venas Umbilicales/citología , Factor A de Crecimiento Endotelial Vascular/farmacología , Factor A de Crecimiento Endotelial Vascular/fisiología
4.
Pharm Res ; 23(6): 1133-43, 2006 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-16715368

RESUMEN

PURPOSE: To evaluate in vitro and computationally model the effects of selected antipsychotic drugs on several ionic currents that contribute to changes in the action potential in cardiac tissue. METHODS: Fourteen antipsychotic drugs or metabolites were examined to determine whether QT interval prolongation could be accounted for by an effect on one or more myocardial ion channels [I(to), I(Na), I(sus), I(K1), and human ether-a-go-go related gene (hERG)]. Using the patch clamp technique, drug effects on these human cardiac currents were tested. RESULTS: All molecules had little inhibitory effect on ion channels (blocking at concentrations >5 microM) other than hERG. A significant correlation was observed between the estimated hERG blockade and the increase in corrected QT for five of the antipsychotics. Molecular modeling identified hydrophobic features related to the interaction with hERG and correctly rank-ordered the test set molecules olanzapine and its metabolites. A network analysis of ligand and protein interactions around hERG using MetaCore (GeneGo Inc., St. Joseph, MI, USA) was used to visualize antipsychotics with affinity for this channel and their interactions with other proteins in this database. CONCLUSION: The antipsychotics do not inhibit the ion channels I(to), I(Na), I(sus), I(K1) to any appreciable extent; however, blockade of hERG is a likely mechanism for the prolongation of the QT interval.


Asunto(s)
Antipsicóticos/farmacología , Electrocardiografía/efectos de los fármacos , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Canales Iónicos/efectos de los fármacos , Miocitos Cardíacos/efectos de los fármacos , Redes Neurales de la Computación , Potenciales de Acción , Anciano , Benzodiazepinas/farmacología , Benzodiazepinas/toxicidad , Línea Celular , Canales de Potasio Éter-A-Go-Go/genética , Canales de Potasio Éter-A-Go-Go/metabolismo , Humanos , Imidazoles/farmacología , Imidazoles/toxicidad , Técnicas In Vitro , Indoles/farmacología , Indoles/toxicidad , Canales Iónicos/metabolismo , Persona de Mediana Edad , Estructura Molecular , Miocitos Cardíacos/metabolismo , Olanzapina , Bloqueadores de los Canales de Potasio/farmacología , Canales de Potasio de Rectificación Interna/efectos de los fármacos , Canales de Potasio de Rectificación Interna/metabolismo , Canales de Sodio/efectos de los fármacos , Canales de Sodio/metabolismo , Relación Estructura-Actividad , Tioridazina/farmacología , Tioridazina/toxicidad , Transfección
5.
Mol Pharmacol ; 63(3): 489-98, 2003 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-12606755

RESUMEN

Organic cation transporters play a critical role in the elimination of therapeutic compounds in the liver and the kidney. We used computational quantitative structure activity approaches to predict molecular features that influence interaction with the human ortholog of the organic cation transporter (hOCT1). [(3)H]tetraethylammonium uptake in HeLa cells stably expressing hOCT1 was inhibited to varying extents by a diverse set of 30 molecules. A subset of 22 of these was used to produce, using Catalyst, a pharmacophore that consisted of three hydrophobic features and a positive ionizable feature. The correlation coefficient of observed versus predicted IC(50) was 0.86 for this training set, which was superior to calculated logP alone (r = 0.73) as a predictor of hOCT1 inhibition. A descriptor-based quantitative structure-activity relationship study using Cerius(2) resulted in an equation relating five molecular descriptors to log IC(50) with a correlation coefficient of 0.95. Furthermore, a group of phenylpyridinium and quinolinium compounds were used to investigate the spatial limitations of the hOCT1 binding site. The affinity for hOCT was higher for 4-phenylpyridiniums > 3-phenylpyridiniums > quinolinium, indicating that substrate affinity was influenced by the distribution of hydrophobic mass. In addition, supraplanar hydrophobic mass was found to increase the affinity for binding hOCT1. These results indicate how a combination of computational and in vitro approaches may yield insight into the binding affinity of transporters and may be applicable to predicting these properties for new therapeutics.


Asunto(s)
Transportador 1 de Catión Orgánico/metabolismo , Compuestos de Piridinio/metabolismo , Compuestos de Quinolinio/metabolismo , Biología Computacional , Células HeLa , Humanos , Modelos Moleculares , Transportador 1 de Catión Orgánico/química , Compuestos de Piridinio/química , Compuestos de Quinolinio/química , Relación Estructura-Actividad , Transfección
6.
J Pharmacol Exp Ther ; 301(2): 427-34, 2002 May.
Artículo en Inglés | MEDLINE | ID: mdl-11961040

RESUMEN

The protein product of the human ether-a-go-go gene (hERG) is a potassium channel that when inhibited by some drugs may lead to cardiac arrhythmia. Previously, a three-dimensional quantitative structure-activity relationship (3D-QSAR) pharmacophore model was constructed using Catalyst with in vitro inhibition data for antipsychotic agents. The rationale of the current study was to use a combination of in vitro and in silico technologies to further test the pharmacophore model and qualitatively predict whether molecules are likely to inhibit this potassium channel. These predictions were assessed with the experimental data using the Spearman's rho rank correlation. The antipsychotic-based hERG inhibitor model produced a statistically significant Spearman's rho of 0.71 for 11 molecules. In addition, 15 molecules from the literature were used as a further test set and were also well ranked by the same model with a statistically significant Spearman's rho value of 0.76. A Catalyst General hERG pharmacophore model was generated with these literature molecules, which contained four hydrophobic features and one positive ionizable feature. Linear regression of log-transformed observed versus predicted IC(50) values for this training set resulted in an r(2) value of 0.90. The model based on literature data was evaluated with the in vitro data generated for the original 22 molecules (including the antipsychotics) and illustrated a significant Spearman's rho of 0.77. Thus, the Catalyst 3D-QSAR approach provides useful qualitative predictions for test set molecules. The model based on literature data therefore provides a potentially valuable tool for discovery chemistry as future molecules may be synthesized that are less likely to inhibit hERG based on information provided by a pharmacophore for the inhibition of this potassium channel.


Asunto(s)
Antipsicóticos/farmacología , Bloqueadores de los Canales de Potasio , Canales de Potasio con Entrada de Voltaje , Antipsicóticos/química , Células Cultivadas , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go , Humanos , Imagenología Tridimensional , Isoxazoles/química , Isoxazoles/farmacología , Modelos Moleculares , Palmitato de Paliperidona , Canales de Potasio/química , Conformación Proteica , Pirimidinas/química , Pirimidinas/farmacología , Reproducibilidad de los Resultados , Relación Estructura-Actividad , Terfenadina/química , Terfenadina/farmacología
7.
Mol Pharmacol ; 61(5): 964-73, 2002 May.
Artículo en Inglés | MEDLINE | ID: mdl-11961113

RESUMEN

P-glycoprotein (P-gp) is an efflux transporter involved in limiting the oral bioavailability and tissue penetration of a variety of structurally divergent molecules. A better understanding of the structural requirements of modulators of P-gp function will aid in the design of therapeutic agents. Toward this goal, three-dimensional quantitative structure-activity relationship (3D-QSAR) models were generated using in vitro data associated with inhibition of P-gp function. Several approaches were undertaken with multiple iterations, yielding Catalyst 3D-QSAR models being able to qualitatively rank-order and predict IC(50) values for P-gp inhibitors excluded from the model in question. The success of these validations suggests that a P-gp pharmacophore for 27 inhibitors of digoxin transport in Caco-2 cells consisted of four hydrophobes and one hydrogen bond acceptor. A second pharmacophore generated with 21 inhibitors of vinblastine binding to plasma membrane vesicles derived from CEM/VLB(100) cells contained three ring aromatic features and one hydrophobic feature. A third pharmacophore generated with 17 inhibitors of vinblastine accumulation in P-gp expressing LLC-PK1 cells contained four hydrophobes and one hydrogen bond acceptor. A final pharmacophore was generated for inhibition of calcein accumulation in P-gp expressing LLC-PK1 cells and found to contain two hydrophobes, a ring aromatic feature, and a hydrogen bond donor. The similarity of features for the pharmacophores of P-gp inhibitors of digoxin transport and vinblastine binding suggest some commonality in their binding sites. Utilization of such models may prove to be of value for prediction of molecules that may modulate one or more P-gp binding sites.


Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/química , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Animales , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Células CACO-2 , Ergonovina/química , Ergonovina/farmacología , Fluoxetina/química , Fluoxetina/farmacología , Humanos , Modelos Moleculares , Oxitócicos/química , Oxitócicos/farmacología , Conformación Proteica , Inhibidores Selectivos de la Recaptación de Serotonina/química , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Relación Estructura-Actividad , Porcinos , Transfección , Vinblastina/química , Vinblastina/farmacología
8.
Mol Pharmacol ; 61(5): 974-81, 2002 May.
Artículo en Inglés | MEDLINE | ID: mdl-11961114

RESUMEN

Using in vitro data, we previously built Catalyst 3-dimensional quantitative structure activity relationship (3D-QSAR) models that qualitatively rank and predict IC(50) values for P-glycoprotein (P-gp) inhibitors. These models were derived and tested with data for inhibition of digoxin transport, calcein accumulation, vinblastine accumulation, and vinblastine binding. In the present study, 16 inhibitors of verapamil binding to P-gp were predicted using these models. These inhibition results were then used to generate a new pharmacophore that consisted of one hydrogen bond acceptor, one ring aromatic feature, and two hydrophobes. This model predicted the rank order of the four data sets described previously and correctly ranked the inhibitory potency of a further four verapamil metabolites identified in the literature. The degree of similarity in rank ordering prediction by these inhibitor pharmacophore models generated to date confirms a likely overlap in the sites to which the three P-gp substrates used in these studies (verapamil, vinblastine, and digoxin) bind. Alignment of the three substrate probes indicated that they are likely to bind the same or overlapping sites within P-gp. Important features on these substrates include multiple hydrophobic and hydrogen bond acceptor features, which are widely dispersed and in agreement among most of the five inhibitor pharmacophores we have described so far. These 3D-QSAR models will be useful for future prediction of likely substrates and inhibitors of P-gp.


Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/química , Verapamilo/farmacología , Vinblastina/farmacología , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Células CACO-2 , Humanos , Modelos Moleculares , Conformación Proteica , Relación Estructura-Actividad , Verapamilo/química , Vinblastina/química
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA