RESUMEN
BACKGROUND: This randomized, placebo-controlled study assessed the safety, tolerability, and immunogenicity of live virus zoster vaccine (ZV) in individuals receiving chronic/maintenance systemic corticosteroid therapy (daily dose equivalent of 5-20mg prednisone) for ≥2 weeks prior to vaccination and ≥6 weeks postvaccination. METHODS: Subjects were followed for adverse experiences (AEs), exposure to varicella or herpes zoster (HZ), or development of varicella/varicella-like or HZ/HZ-like rashes for 42 days postvaccination (primary safety follow-up period) and for serious AEs (SAEs) through Day 182 postvaccination (secondary follow-up period). Varicella-zoster virus (VZV) antibody titers by glycoprotein enzyme-linked immunosorbent assay (gpELISA) were measured at baseline and at Week 6 postvaccination. RESULTS: The proportions of subjects reporting systemic AEs and SAEs were similar in both groups. A higher percentage of subjects reported injection-site AEs in the ZV group (21.5%) than in the placebo group (12.1%). One SAE of ophthalmic HZ (onset Day 16 postvaccination) was reported in the ZV group and deemed vaccine-related by the study investigator; however, PCR testing confirmed the presence of wild-type (not vaccine strain) VZV. Geometric mean titer (GMT) at 6 weeks postvaccination was higher for ZV recipients than placebo recipients, with estimated geometric mean fold rises (GMFR) of 2.3 (CI: 2.0, 2.7) and 1.1 (CI: 1.0, 1.2) respectfully. CONCLUSIONS: In adults ≥60 years old on chronic/maintenance corticosteroids, ZV was generally well tolerated and immunogenic. The VZV-specific gpELISA antibody GMT at 6 weeks postvaccination and the GMFR from baseline to 6 weeks postvaccination were higher in the ZV group than in the placebo group.
Asunto(s)
Corticoesteroides/uso terapéutico , Vacuna contra el Herpes Zóster/efectos adversos , Vacuna contra el Herpes Zóster/inmunología , Inmunosupresores/uso terapéutico , Anciano , Anciano de 80 o más Años , Anticuerpos Antivirales/sangre , Varicela/epidemiología , Varicela/prevención & control , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Ensayo de Inmunoadsorción Enzimática , Femenino , Estudios de Seguimiento , Herpes Zóster/epidemiología , Herpes Zóster/prevención & control , Vacuna contra el Herpes Zóster/administración & dosificación , Humanos , Masculino , Persona de Mediana Edad , Placebos/administración & dosificación , Vacunas Atenuadas/administración & dosificación , Vacunas Atenuadas/efectos adversos , Vacunas Atenuadas/inmunologíaRESUMEN
BACKGROUND: Prior clinical studies of zoster vaccine enrolled subjects without a history of herpes zoster (HZ), so there are limited data on safety and immunogenicity in vaccinees with a prior history of HZ. This study was conducted to evaluate the safety and immunogenicity of zoster vaccine recipients who had a prior episode of HZ. METHODS: A total of 101 subjects > or = 50 years of age with a prior history of HZ were enrolled. They were stratified by number of years since their HZ (5 to 9 years and > or = 10 years, in an approximate 2:1 ratio), and randomized 1:1 to one of two vaccination groups. On day 1, Group I was administered zoster vaccine and Group II received placebo. At week 4, Group I received placebo and Group II received zoster vaccine. Subjects were followed for adverse experiences (AEs), exposure to varicella or HZ, and development of any varicella/varicella-like or HZ/HZ-like rashes, for 28 days after each injection. Blood samples were obtained prior to study injection on day 1 and week 4, and at week 8. Serum was assessed for varicella-zoster virus (VZV) antibody concentration by glycoprotein enzyme-linked immunosorbent assay. RESULTS: No serious AEs were reported within the 28-day safety follow-up period following any vaccination. Although a higher percentage of subjects reported injection-site AEs after receiving zoster vaccine than did placebo recipients, the proportion of subjects reporting systemic clinical AEs was similar in both groups. Zoster vaccine induced a VZV antibody response at 4 weeks post-vaccination. The estimated geometric mean titer (GMT) ratio (vaccine/placebo) was 2.07 (95% CI: 1.48, 2.88). The geometric mean fold-rise (GMFR) from prevaccination to week 4 post-vaccination was 2.1 in zoster vaccine recipients, versus 1.0 in placebo recipients. CONCLUSIONS: In HZ history-positive adults > or = 50 years of age, zoster vaccine: (1) was well tolerated; and (2) significantly boosted the level of VZV antibody from baseline to 4 weeks post-vaccination as measured by GMT and GMFR. These data support the Advisory Committee on Immunization Practices' recommendation for routine zoster vaccination for all immunocompetent persons >/=60 years of age irrespective of HZ history.
Asunto(s)
Vacuna contra el Herpes Zóster/inmunología , Herpes Zóster/prevención & control , Anciano , Anciano de 80 o más Años , Anticuerpos Antivirales/sangre , Formación de Anticuerpos , Estudios Cruzados , Método Doble Ciego , Femenino , Herpes Zóster/inmunología , Vacuna contra el Herpes Zóster/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Estados UnidosRESUMEN
Pyrimidino-thiazolyl carbonitriles were prepared that are potent VEGFR-2 (KDR) kinase inhibitors. The modification of lead structures resulted in 3m which exhibited the best overall profile in KDR inhibitory activity, iv/po pharmacokinetics, and reduced hERG affinity.
Asunto(s)
Nitrilos/síntesis química , Nitrilos/farmacología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/síntesis química , Pirimidinas/farmacología , Tiazoles/síntesis química , Tiazoles/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Animales , Perros , Macaca mulatta , Estructura Molecular , Nitrilos/química , Inhibidores de Proteínas Quinasas/química , Pirimidinas/química , Ratas , Sensibilidad y Especificidad , Relación Estructura-Actividad , Tiazoles/química , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
A series of N-(1,3-thiazol-2-yl)pyridin-2-amine KDR kinase inhibitors have been developed that possess optimal properties. Compounds have been discovered that exhibit excellent in vivo potency. The particular challenges of overcoming hERG binding activity and QTc increases in vivo in addition to achieving good pharmacokinetics have been acomplished by discovering a unique class of amine substituents. These compounds have a favorable kinase selectivity profile that can be accentuated with appropriate substitution.
Asunto(s)
Aminopiridinas/síntesis química , Canales de Potasio con Entrada de Voltaje/metabolismo , Piridinas/síntesis química , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Tiazoles/síntesis química , Administración Oral , Aminopiridinas/farmacocinética , Aminopiridinas/farmacología , Animales , Disponibilidad Biológica , Línea Celular , Perros , Canal de Potasio ERG1 , Electrocardiografía/efectos de los fármacos , Canales de Potasio Éter-A-Go-Go , Técnicas In Vitro , Pulmón/enzimología , Macaca mulatta , Masculino , Ratones , Microsomas Hepáticos/metabolismo , Fosforilación , Piridinas/farmacocinética , Piridinas/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Tiazoles/farmacocinética , Tiazoles/farmacología , Distribución Tisular , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
An azo-dye lead was modified to a novel N-(1,3-thiazol-2-yl)pyridin-2-amine series of KDR kinase inhibitors through the use of rapid analog libraries. This new class has been found to be potent, selective, and of low molecular weight. Molecular modeling has postulated an interesting conformational preference and binding mode for these compounds in the active site of the enzyme.
Asunto(s)
Aminas/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Aminas/síntesis química , Sitios de Unión , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Humanos , Concentración 50 Inhibidora , Modelos Moleculares , Unión Proteica , Conformación Proteica/efectos de los fármacos , Relación Estructura-Actividad , Termodinámica , Receptor 2 de Factores de Crecimiento Endotelial Vascular/químicaRESUMEN
3,7-Diarylsubstituted imidazopyridines were designed and developed as a new class of KDR kinase inhibitors. A variety of imidazopyridines were synthesized and potent inhibitors of KDR kinase activity were identified with good aqueous solubility.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Diseño de Fármacos , Humanos , Estructura Molecular , Solubilidad , Relación Estructura-ActividadRESUMEN
Small molecule inhibitors of KDR kinase activity have typically possessed poor intrinsic physical properties including low aqueous solubility and high lipophilicity. These features have often conferred limited cell permeability manifested in low levels of cell-based KDR inhibitory activity and oral bioavailability. Thus, the design of inhibitors with appropriate physical properties has played a critical role in the development of clinical candidates. We present a variety of structural modifications that have afforded improvements in physical properties and thereby have addressed suboptimal cellular potency and pharmacokinetics for three unique classes of KDR kinase inhibitors.
Asunto(s)
Diseño de Fármacos , Inhibidores Enzimáticos/química , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Animales , Sitios de Unión , Disponibilidad Biológica , Permeabilidad de la Membrana Celular , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Modelos Moleculares , Estructura Molecular , Solubilidad , Relación Estructura-Actividad , Receptor 2 de Factores de Crecimiento Endotelial Vascular/químicaRESUMEN
Modifications to the basic side-chain of early lead structures of the indolyl quinolinone class of KDR kinase inhibitors resulted in improved pharmacokinetic and ancillary profiles. Specifically, compounds bearing 5-amido- and 5-sulphonamido-indolyl substituents exhibited lower plasma clearance and weaker binding affinity for the I(Kr) potassium channel hERG.
Asunto(s)
Proteínas de Transporte de Catión/metabolismo , Inhibidores Enzimáticos/farmacocinética , Canales de Potasio con Entrada de Voltaje , Canales de Potasio/metabolismo , Quinolonas/farmacocinética , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Animales , Línea Celular , Perros , Inhibidores Enzimáticos/química , Canales de Potasio Éter-A-Go-Go , Humanos , Microsomas Hepáticos/enzimología , Unión Proteica/fisiología , Quinolonas/química , Ratas , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
We have discovered 3-(5-thien-3-ylpyridin-3-yl)-1H-indoles as potent inhibitors of KDR kinase activity. This communication details the evolution of this novel class from a potent screening lead of vastly different structure with an emphasis on structural modifications that retained activity and provided improvements in key physical properties. The synthesis and in-depth evaluation of these inhibitors are described.
Asunto(s)
Inhibidores de la Angiogénesis/síntesis química , Indoles/síntesis química , Indoles/farmacocinética , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Administración Oral , Inhibidores de la Angiogénesis/farmacocinética , Inhibidores de la Angiogénesis/farmacología , Animales , Disponibilidad Biológica , Línea Celular , Semivida , Indoles/farmacología , Concentración 50 Inhibidora , Ratas , Relación Estructura-ActividadRESUMEN
1,5-Diarylbenzimidazoles have been identified as potent inhibitors of KDR kinase activity. The series was developed with a goal of finding compounds with optimal drug-like properties. This communication describes structural modifications in the series that enhance solubility, lower protein binding, and provide compounds with excellent potency and pharmacokinetic profiles.
Asunto(s)
Bencimidazoles/síntesis química , Bencimidazoles/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Animales , Fenómenos Químicos , Química Física , Perros , Diseño de Fármacos , Inhibidores Enzimáticos/farmacocinética , Semivida , Concentración de Iones de Hidrógeno , Indicadores y Reactivos , Conformación Molecular , Ratas , Relación Estructura-ActividadRESUMEN
2,4-Disubstituted pyrimidines were synthesized as a novel class of KDR kinase inhibitors. Evaluation of the SAR of the screening lead compound 1 (KDR IC(50)=105 nM, Cell IC(50)=8% inhibition at 500 nM) led to the potent 3,5-dimethylaniline derivative 2d (KDR IC(50)=6 nM, cell IC(50)=19 nM).
Asunto(s)
Inhibidores de la Angiogénesis/síntesis química , Pirimidinas/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Inhibidores de la Angiogénesis/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Células Cultivadas , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Humanos , Concentración 50 Inhibidora , Pirimidinas/síntesis química , Relación Estructura-ActividadRESUMEN
We have introduced solubilizing functionality to a 3,6-disubstituted pyrazolo[1,5-a]pyrimidine series of KDR kinase inhibitors to improve the physical properties of these compounds. The addition of a basic side-chain to the 6-aryl ring, introduction of 3-pyridyl groups, and most significantly, incorporation of a 4-pyridinonyl substituent at the 6-position of the core are modifications that maintain and often enhance the intrinsic potency of this class of inhibitors. Moreover, the improvements in physical properties result in marked increases in cellular activity and more favorable pharmacokinetics in rats. The synthesis and SAR of these compounds are described.
Asunto(s)
Inhibidores de la Angiogénesis/síntesis química , Pirimidinas/farmacocinética , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Inhibidores de la Angiogénesis/farmacocinética , Inhibidores de la Angiogénesis/farmacología , Animales , División Celular/efectos de los fármacos , Línea Celular , Endotelio Vascular/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Humanos , Concentración 50 Inhibidora , Tasa de Depuración Metabólica , Farmacocinética , Pirimidinas/síntesis química , Pirimidinas/farmacología , Ratas , Solubilidad , Relación Estructura-ActividadRESUMEN
We have synthesized and evaluated the activity of 3,6-disubstituted pyrazolo[1,5-a]pyrimidines as a new class of KDR kinase inhibitors. Starting with screening lead 1, potency against isolated KDR was fully optimized with 3-thienyl and 4-methoxyphenyl substituents at the 6- and 3-positions (3g, KDR IC(50)=19 nM), respectively. The synthesis and SAR of these compounds are described.