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/farmacologíaRESUMEN
The design, synthesis, and SAR of a series of substituted spirohydantoins are described. Optimization of an in-house screening hit gave compounds that exhibited potent binding affinity and functional activity at MCH-R1.
Asunto(s)
Fármacos Antiobesidad/síntesis química , Hidantoínas/síntesis química , Receptores de la Hormona Hipofisaria/antagonistas & inhibidores , Compuestos de Espiro/síntesis química , Fármacos Antiobesidad/farmacología , Diseño de Fármacos , Humanos , Hidantoínas/farmacología , Cinética , Unión Proteica , Compuestos de Espiro/farmacología , Relación Estructura-ActividadRESUMEN
A series of thienopyrimidinone bis-aminopyrrolidine ureas were designed, synthesized, and evaluated for their ability to bind melanin-concentrating hormone receptor-1. These compounds exhibit potent binding affinity (K(i)=3 nM) and good in vitro metabolic stability.
Asunto(s)
Química Farmacéutica/métodos , Pirrolidinas/química , Receptores de Somatostatina/antagonistas & inhibidores , Urea/análogos & derivados , Urea/química , Animales , Inhibidores del Citocromo P-450 CYP2D6 , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Cinética , Ratones , Modelos Químicos , Conformación Molecular , Unión Proteica , Relación Estructura-ActividadRESUMEN
The design, synthesis, and SAR of a series of retro bis-aminopyrrolidine ureas are described. Compounds from this series exhibited considerable binding affinity (Ki = 1 nM) and functional activity at MCH-R1, acceptable CYP2D6 inhibition, and good rat brain exposure.
Asunto(s)
Pirrolidinas/química , Pirrolidinas/farmacología , Receptores de Somatostatina/antagonistas & inhibidores , Urea/análogos & derivados , Animales , Concentración 50 Inhibidora , Estructura Molecular , Pirrolidinas/síntesis química , Pirrolidinas/farmacocinética , Ratas , Receptores de Somatostatina/metabolismo , Relación Estructura-Actividad , Urea/síntesis química , Urea/química , Urea/farmacocinética , Urea/farmacologíaRESUMEN
The design, synthesis, and SAR of a series of retro bis-aminopyrrolidine ureas are described. Compounds from this series exhibited potent binding affinity and functional activity at MCH-R1, and good oral bioavailability in rat.
Asunto(s)
Pirrolidinas/síntesis química , Pirrolidinas/farmacología , Receptores de la Hormona Hipofisaria/antagonistas & inhibidores , Urea/análogos & derivados , Animales , Estructura Molecular , Pirrolidinas/química , Ratas , Receptores de la Hormona Hipofisaria/metabolismo , Relación Estructura-Actividad , Urea/síntesis química , Urea/química , Urea/farmacologíaRESUMEN
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/farmacologíaRESUMEN
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).