RESUMEN
Our research on hydantoin based TNF-α converting enzyme (TACE) inhibitors has led to an acetylene containing series that demonstrates sub-nanomolar potency (K(i)) as well as excellent activity in human whole blood. These studies led to the discovery of highly potent TACE inhibitors with good DMPK profiles.
Asunto(s)
Proteínas ADAM/antagonistas & inhibidores , Antiinflamatorios/química , Artritis Reumatoide/tratamiento farmacológico , Inhibidores de Proteasas/química , Proteínas ADAM/metabolismo , Proteína ADAM17 , Acetileno/análogos & derivados , Acetileno/farmacocinética , Acetileno/uso terapéutico , Animales , Antiinflamatorios/farmacocinética , Antiinflamatorios/uso terapéutico , Perros , Haplorrinos , Humanos , Inhibidores de Proteasas/farmacocinética , Inhibidores de Proteasas/uso terapéutico , RatasRESUMEN
We disclose further optimization of hydantoin TNF-alpha convertase enzyme (TACE) inhibitors. SAR with respect to the non-prime region of TACE active site was explored. A series of biaryl substituted hydantoin compounds was shown to have sub-nanomolar K(i), good rat PK, and good selectivity versus MMP-1, -2, -3, -7, -9, and -13.
Asunto(s)
Proteínas ADAM/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Proteína ADAM17 , Animales , Ratas , Relación Estructura-ActividadRESUMEN
We disclose inhibitors of TNF-alpha converting enzyme (TACE) designed around a hydantoin zinc binding moiety. Crystal structures of inhibitors bound to TACE revealed monodentate coordination of the hydantoin to the zinc. SAR, X-ray, and modeling designs are described. To our knowledge, these are the first reported X-ray structures of TACE with a hydantoin zinc ligand.
