RESUMEN
In a series of bradykinin B1 antagonists, we discovered that replacement of oxopiperazine acetamides with dehydro-oxopiperazine acetamides provided compounds with enhanced activity against the B1 receptor. The synthesis and SAR leading to potent analogs with reduced molecular weight will be discussed.
Asunto(s)
Acetamidas/farmacología , Antagonistas del Receptor de Bradiquinina B1 , Piperazinas/farmacología , Acetamidas/síntesis química , Acetamidas/química , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Piperazinas/síntesis química , Piperazinas/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The insulin-like growth factor-1 receptor (IGF-1R) plays an important role in the regulation of cell growth and differentiation, and in protection from apoptosis. IGF-1R has been shown to be an appealing target for the treatment of human cancer. Herein, we report the synthesis, structure-activity relationships (SAR), X-ray cocrystal structure and in vivo tumor study results for a series of 2,4-bis-arylamino-1,3-pyrimidines.
Asunto(s)
Inhibidores de Proteínas Quinasas/química , Pirimidinas/química , Quinolinas/síntesis química , Receptor IGF Tipo 1/antagonistas & inhibidores , Animales , Sitios de Unión , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Humanos , Ratones , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Pirimidinas/síntesis química , Pirimidinas/farmacocinética , Quinolinas/química , Quinolinas/farmacocinética , Receptor IGF Tipo 1/metabolismo , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Thiazolones with an exo-norbornylamine at the 2-position and an isopropyl group on the 5-position are potent 11beta-HSD1 inhibitors. However, the C-5 center was prone to epimerization in vitro and in vivo, forming a less potent diastereomer. A methyl group was added to the C-5 position to eliminate epimerization, leading to the discovery of (S)-2-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-ylamino)-5-isopropyl-5-methylthiazol-4(5H)-one (AMG 221). This compound decreased fed blood glucose and insulin levels and reduced body weight in diet-induced obesity mice.