RESUMEN
The identification and hit-to-lead exploration of a novel, potent and selective series of histamine H(4) receptor inverse agonists is described. The initial hit, 3A (IC(50) 19 nM) was identified by means of a ligand-based virtual screening approach. Subsequent medicinal chemistry exploration yielded 18I which possessed increased potency (R-enantiomer IC(50) 1 nM) as well as enhanced microsomal stability.
Asunto(s)
Antagonistas de los Receptores Histamínicos/farmacología , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Animales , Disponibilidad Biológica , Descubrimiento de Drogas , Antagonistas de los Receptores Histamínicos/química , Antagonistas de los Receptores Histamínicos/farmacocinética , Concentración 50 Inhibidora , Macaca fascicularis , Ratas , Receptores Histamínicos , Receptores Histamínicos H4 , EstereoisomerismoRESUMEN
A series of pyrimidine nitrile inhibitors of Cathepsin K with reduced glutathione reactivity has been identified and Molecular Core Matching (MoCoM) has been used to quantify the effect of an amino substituent at C5.
Asunto(s)
Catepsinas/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/síntesis química , Nitrilos/síntesis química , Catepsina K , Catepsinas/química , Química Farmacéutica/métodos , Inhibidores de Cisteína Proteinasa/farmacología , Diseño de Fármacos , Humanos , Lisosomas/enzimología , Modelos Químicos , Estructura Molecular , Osteoartritis/tratamiento farmacológico , Osteoclastos , Osteoporosis/tratamiento farmacológico , Pirimidinas/química , Relación Estructura-Actividad , Tecnología Farmacéutica/métodosRESUMEN
Addition of the 4-fluorophenylpyrazole group to the previously described 2-azadecalin glucocorticoid receptor (GR) antagonist 1 resulted in significantly enhanced functional activity. SAR of the bridgehead substituent indicated that whereas groups as small as methyl afforded high GR binding, GR functional activity was enhanced by larger groups such as benzyl, substituted ethers, and aminoalkyl derivatives. GR antagonists with binding and functional activity comparable to mifepristone were discovered (e.g., 52: GR binding K(i) 0.7 nM; GR reporter gene functional K(i) 0.6 nM) and found to be highly selective over other steroid receptors. Analogues 43 and 45 had >50% oral bioavailability in the dog.
