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1.
J Med Chem ; 55(7): 3250-60, 2012 Apr 12.
Artículo en Inglés | MEDLINE | ID: mdl-22380736

RESUMEN

Serine/threonine protein kinases Aurora A, B, and C play essential roles in cell mitosis and cytokinesis. Currently a number of Aurora kinase inhibitors with different isoform selectivities are being evaluated in the clinic. Herein we report the discovery and characterization of 21c (AC014) and 21i (AC081), two structurally novel, potent, kinome-selective pan-Aurora inhibitors. In the human colon cancer cell line HCT-116, both compounds potently inhibit histone H3 phosphorylation and cell proliferation while inducing 8N polyploidy. Both compounds administered intravenously on intermittent schedules displayed potent and durable antitumor activity in a nude rat HCT-116 tumor xenograft model and exhibited good in vivo tolerability. Taken together, these data support further development of both 21c and 21i as potential therapeutic agents for the treatment of solid tumors and hematological malignancies.


Asunto(s)
Acetanilidas/síntesis química , Antineoplásicos/síntesis química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Triazinas/síntesis química , Acetanilidas/farmacocinética , Acetanilidas/farmacología , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Aurora Quinasa A , Aurora Quinasas , Dominio Catalítico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Histonas/metabolismo , Humanos , Modelos Moleculares , Trasplante de Neoplasias , Fosforilación , Unión Proteica , Ratas , Ratas Desnudas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad , Trasplante Heterólogo , Triazinas/farmacocinética , Triazinas/farmacología
6.
Bioorg Med Chem Lett ; 15(14): 3439-45, 2005 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-15950467

RESUMEN

A novel series of bis-aminopyrrolidine ureas containing either a 4-biphenylcarboxmide or 5-phenyl-2-thiophenecarboxamide group have been identified as potent and functional antagonists of the melanin-concentrating hormone receptor-1. Syntheses and SAR are described, which led to the discovery of compounds with high binding affinity (Ki = 1 nM) for the receptor. Preliminary in vitro metabolic stability data are also reported for key compounds.


Asunto(s)
Amidas , Pirrolidinas , Receptores de Somatostatina/antagonistas & inhibidores , Urea , Amidas/síntesis química , Amidas/farmacología , Animales , Diseño de Fármacos , Conformación Molecular , Peso Molecular , Pirrolidinas/síntesis química , Pirrolidinas/farmacología , Ratas , Relación Estructura-Actividad , Urea/análogos & derivados , Urea/síntesis química , Urea/farmacología
7.
Bioorg Med Chem Lett ; 15(4): 999-1004, 2005 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-15686900

RESUMEN

Ureas derived from two substituted 3-aminopyrrolidine subunits were prepared as constrained analogs of a linear lead compound and tested as antagonists of the MCH(1) receptor. The series was optimized for substitution and stereochemistry to generate a functional antagonist with a K(i) of 3.3 nM and IC(50) of 12 nM (GTPgammaS).


Asunto(s)
Receptores de la Hormona Hipofisaria/antagonistas & inhibidores , Urea/química , Urea/farmacología , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Humanos , Pirrolidinas/química , Pirrolidinas/farmacología , Estereoisomerismo , Relación Estructura-Actividad
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