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1.
Pediatr Exerc Sci ; 35(4): 206-213, 2023 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-36596308

RESUMEN

PURPOSE: Examine the reliability of field-based fitness assessments in school-aged children with emotional or behavioral difficulties (EBD). Understanding the impact of fitness on physical activity participation for children with EBD is limited by our ability to reliably measure it. METHODS: Fifteen children aged 7-12 years with EBD completed 7 assessments-standing broad jump, overhead throw, grip strength, isometric plank hold, isometric wall squat, unilateral heel raise, and modified 6-minute walk test-in a random order on 2 separate occasions. Intraclass correlation coefficients (ICCs) were computed to evaluate reliability. RESULTS: ICCs ranged from .65 to .99 representing moderate to excellent reliability for all assessments. Shorter assessments requiring less attention and behavior regulation tended to demonstrate higher ICC values while assessments with greater attention or behavioral regulation demands tended to have lower ICC values. CONCLUSION: Results demonstrate varied reliability for fitness tests in children with EBD. Practitioners can use grip strength and standing broad jump assessments with confidence. Other assessments have good reliability but greater variability indicating they may be a challenge for some children with EBD.


Asunto(s)
Prueba de Esfuerzo , Ejercicio Físico , Humanos , Niño , Prueba de Esfuerzo/métodos , Reproducibilidad de los Resultados , Fuerza de la Mano , Postura , Aptitud Física/fisiología , Fuerza Muscular/fisiología
2.
Nat Chem Biol ; 11(7): 525-31, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-26006010

RESUMEN

Drugs with prolonged on-target residence times often show superior efficacy, yet general strategies for optimizing drug-target residence time are lacking. Here we made progress toward this elusive goal by targeting a noncatalytic cysteine in Bruton's tyrosine kinase (BTK) with reversible covalent inhibitors. Using an inverted orientation of the cysteine-reactive cyanoacrylamide electrophile, we identified potent and selective BTK inhibitors that demonstrated biochemical residence times spanning from minutes to 7 d. An inverted cyanoacrylamide with prolonged residence time in vivo remained bound to BTK for more than 18 h after clearance from the circulation. The inverted cyanoacrylamide strategy was further used to discover fibroblast growth factor receptor (FGFR) kinase inhibitors with residence times of several days, demonstrating the generalizability of the approach. Targeting of noncatalytic cysteines with inverted cyanoacrylamides may serve as a broadly applicable platform that facilitates 'residence time by design', the ability to modulate and improve the duration of target engagement in vivo.


Asunto(s)
Acrilamidas/farmacocinética , Linfocitos B/efectos de los fármacos , Cianoacrilatos/farmacocinética , Inhibidores de Proteínas Quinasas/farmacocinética , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Acrilamidas/síntesis química , Agammaglobulinemia Tirosina Quinasa , Animales , Linfocitos B/enzimología , Linfocitos B/patología , Línea Celular Tumoral , Cristalografía por Rayos X , Cianoacrilatos/síntesis química , Dasatinib , Femenino , Expresión Génica , Humanos , Ligandos , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Estructura Terciaria de Proteína , Proteínas Tirosina Quinasas/química , Proteínas Tirosina Quinasas/genética , Pirimidinas/farmacocinética , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Células Sf9 , Spodoptera , Relación Estructura-Actividad , Especificidad por Sustrato , Tiazoles/farmacocinética , Factores de Tiempo
3.
Bioorg Med Chem Lett ; 22(1): 300-4, 2012 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-22119470

RESUMEN

The discovery and optimization of a novel class of quinolone small-molecules that inhibit NS5B polymerase, a key enzyme of the HCV viral life-cycle, is described. Our research led to the replacement of a hydrolytically labile ester functionality with bio-isosteric heterocycles. An X-ray crystal structure of a key analog bound to NS5B facilitated the optimization of this series of compounds to afford increased activity against the target enzyme and in the cell-based replicon assay system.


Asunto(s)
Antivirales/farmacología , Química Farmacéutica/métodos , Hepacivirus/enzimología , Quinolonas/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Sitio Alostérico , Antivirales/síntesis química , Sitios de Unión , Cristalografía por Rayos X/métodos , Diseño de Fármacos , Enlace de Hidrógeno , Hidrólisis , Concentración 50 Inhibidora , Modelos Químicos , Conformación Molecular , Quinolonas/síntesis química , Relación Estructura-Actividad , Proteínas no Estructurales Virales/química , Rayos X
4.
J Med Chem ; 65(7): 5300-5316, 2022 04 14.
Artículo en Inglés | MEDLINE | ID: mdl-35302767

RESUMEN

Bruton's tyrosine kinase (BTK), a Tec family tyrosine kinase, is critical in immune pathways as an essential intracellular signaling element, participating in both adaptive and immune responses. Currently approved BTK inhibitors are irreversible covalent inhibitors and limited to oncology indications. Herein, we describe the design of covalent reversible BTK inhibitors and the discoveries of PRN473 (11) and rilzabrutinib (PRN1008, 12). These compounds have exhibited potent and durable inhibition of BTK, in vivo efficacy in rodent arthritis models, and clinical efficacy in canine pemphigus foliaceus. Compound 11 has completed phase 1 trials as a topical agent, and 12 is in phase 3 trials for pemphigus vulgaris and immune thrombocytopenia.


Asunto(s)
Inhibidores de Proteínas Quinasas , Transducción de Señal , Agammaglobulinemia Tirosina Quinasa , Animales , Perros , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico
5.
Bioorg Med Chem Lett ; 21(1): 82-7, 2011 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-21145235

RESUMEN

Hepatitis C virus (HCV) infection is treated with a combination of peginterferon alfa-2a/b and ribavirin. To address the limitations of this therapy, numerous small molecule agents are in development, which act by directly affecting key steps in the viral life-cycle. Herein we describe our discovery of quinolone derivatives, novel small-molecules that inhibit NS5b polymerase, a key enzyme of the viral life-cycle. A crystal structure of a quinoline analog bound to NS5B reveals that this class of compounds binds to allosteric site-II (non-nucleoside inhibitor-site 2, NNI-2) of this protein.


Asunto(s)
Antivirales/química , Inhibidores Enzimáticos/química , Hepacivirus/enzimología , Quinolonas/química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Regulación Alostérica , Antivirales/síntesis química , Antivirales/farmacología , Sitios de Unión , Simulación por Computador , Cristalografía por Rayos X , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Quinolonas/síntesis química , Quinolonas/farmacología , Relación Estructura-Actividad , Proteínas no Estructurales Virales/metabolismo
6.
J Med Chem ; 60(15): 6516-6527, 2017 08 10.
Artículo en Inglés | MEDLINE | ID: mdl-28665128

RESUMEN

Aberrant signaling of the FGF/FGFR pathway occurs frequently in cancers and is an oncogenic driver in many solid tumors. Clinical validation of FGFR as a therapeutic target has been demonstrated in bladder, liver, lung, breast, and gastric cancers. Our goal was to develop an irreversible covalent inhibitor of FGFR1-4 for use in oncology indications. An irreversible covalent binding mechanism imparts many desirable pharmacological benefits including high potency, selectivity, and prolonged target inhibition. Herein we report the structure-based design, medicinal chemistry optimization, and unique ADME assays of our irreversible covalent drug discovery program which culminated in the discovery of compound 34 (PRN1371), a highly selective and potent FGFR1-4 inhibitor.


Asunto(s)
Antineoplásicos/farmacología , Neoplasias/tratamiento farmacológico , Piridonas/farmacología , Pirimidinas/farmacología , Receptores de Factores de Crecimiento de Fibroblastos/antagonistas & inhibidores , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/síntesis química , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Perros , Diseño de Fármacos , Estabilidad de Medicamentos , Femenino , Humanos , Absorción Intestinal , Macaca fascicularis , Masculino , Piridonas/administración & dosificación , Piridonas/síntesis química , Piridonas/farmacocinética , Pirimidinas/administración & dosificación , Pirimidinas/síntesis química , Pirimidinas/farmacocinética , Ratas Sprague-Dawley , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Receptor Tipo 3 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Receptor Tipo 4 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Solubilidad , Relación Estructura-Actividad
7.
J Med Chem ; 57(5): 1964-75, 2014 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-24224729

RESUMEN

By reducing the basicity of the core heterocycle in a series of HCV NS5B inhibitors, the hERG liability was reduced. The SAR was then systematically explored in order to increase solubility and enable dose escalation while retaining potency. During this exploration, a facile decarboxylation was noted and was exploited as a novel prodrug mechanism. The synthesis and characterization of these prodrugs and their utilization in chronic toxicity studies are presented.


Asunto(s)
Antivirales/farmacología , Inhibidores Enzimáticos/farmacología , Hepacivirus/efectos de los fármacos , Piridazinas/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Antivirales/química , Antivirales/farmacocinética , Perros , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Hepacivirus/enzimología , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Piridazinas/química , Piridazinas/farmacocinética , Ratas , Relación Estructura-Actividad
9.
Bioorg Med Chem Lett ; 16(6): 1596-600, 2006 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-16413783

RESUMEN

Within the trypsin family of coagulation proteases, obtaining highly selective inhibitors of factor VIIa has been challenging. We report a series of factor VIIa (fVIIa) inhibitors based on the 5-amidino-2-(2-hydroxy-biphenyl-3-yl)-benzimidazole (1) scaffold with potency for fVIIa and high selectivity against factors IIa, Xa, and trypsin. With this scaffold class, we propose that a unique hydrogen bond interaction between a hydroxyl on the distal ring of the biaryl system and the backbone carbonyl of fVIIa lysine-192 provides a basis for enhanced selectivity and potency for fVIIa.


Asunto(s)
Factor VIIa/antagonistas & inhibidores , Sitios de Unión , Inhibidores del Factor Xa , Humanos , Enlace de Hidrógeno , Unión Proteica , Protrombina/antagonistas & inhibidores , Relación Estructura-Actividad , Tripsina/metabolismo
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