RESUMEN
We have discovered nanomolar inhibitors of TNF-alpha convertase (TACE) comprised of a novel spirocyclic scaffold and either a carboxylate or hydroxamate zinc binding moiety. X-ray crystal structures and computer models of selected compounds binding to TACE explain the observed SAR. We report the first TACE X-ray crystal structure for an inhibitor with a carboxylate zinc ligand.
Asunto(s)
Proteínas ADAM/antagonistas & inhibidores , Ácidos Carboxílicos/química , Ácidos Hidroxámicos/química , Proteína ADAM17 , Ácidos Carboxílicos/farmacología , Simulación por Computador , Cristalografía por Rayos X , Ácidos Hidroxámicos/farmacología , Ligandos , Modelos Moleculares , Unión Proteica , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Relación Estructura-Actividad , ZincRESUMEN
Structure-activity relationship on our recently reported triaryl bis-sulfone class of cannabinoid-2 (CB2) receptor selective inverse agonists was explored. Modifications to the methane sulfonamide, substitutions to B and C phenyl rings, and replacements of the C-ring were investigated. A compound with excellent CB2 activity, selectivity for CB2 over CB1, and in vivo plasma levels was identified.
Asunto(s)
Química Farmacéutica/métodos , Receptor Cannabinoide CB2/química , Sulfonas/química , Animales , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Cinética , Ligandos , Modelos Químicos , Unión Proteica , Ratas , Receptores de Droga , Sodio/química , Relación Estructura-ActividadRESUMEN
A novel series of histamine H(3) receptor antagonists, based on the 4-benzyl-(1H-imidazole-4-yl) template, incorporating urea and carbamate linkers has been prepared. Compound 3j is a selective H(3) antagonist and demonstrates excellent oral plasma levels in the rat and monkey.