RESUMEN
A novel series of indazole non-steroidal glucocorticoid receptor agonist has been discovered. This series features a sulfonamide central core and meta amides which interact with the extended ligand binding domain. This series has produced some of the most potent and least lipophilic agonists of which we are aware such as 20a (NFκB pIC(50) 8.3 (100%), clogP 1.9). Certain analogues in this series also display evidence for modulated pharmacology.
Asunto(s)
Indazoles/química , Receptores de Glucocorticoides/agonistas , Sulfonamidas/síntesis química , Sitios de Unión , Línea Celular Tumoral , Simulación por Computador , Evaluación Preclínica de Medicamentos , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Indazoles/síntesis química , Indazoles/farmacología , Receptores de Glucocorticoides/metabolismo , Relación Estructura-Actividad , Sulfonamidas/farmacologíaRESUMEN
Aryl aminopyrazole amides capped with N-alkylbenzamides 13-16 are selective glucocorticoid receptor agonists. 2,6-Disubstituted benzamides have prednisolone-like potency or better in vitro. Good oral exposure was demonstrated in the rat, with compounds with lower lipophilicity, for example N-hydroxyethyl benzamides (e.g., 16e).