RESUMEN
Using computer aided modelling studies, a new extended P2/S2 interaction was identified. This extended region can accommodate a variety of functional groups, such as aryls and basic amines. It was discovered that the N3 nitrogen of the pyrimidine-2-carbonitrile is critical for its cathepsin cysteine protease inhibition. N1 nitrogen also contributes to the inhibitory activity, but to a very limited degree. An 'in situ double activation' mechanism was proposed to explain these results.
Asunto(s)
Catepsinas/antagonistas & inhibidores , Nitrilos/química , Inhibidores de Proteasas/química , Pirimidinas/química , Sitios de Unión , Catepsinas/metabolismo , Simulación por Computador , Humanos , Modelos Moleculares , Nitrilos/síntesis química , Nitrilos/farmacología , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacologíaRESUMEN
The trifluoromethylphenyl P2 motif from previously reported heteroarylnitrile series has been successfully applied for the design and synthesis of highly potent novel ketoamide-based cathepsin S inhibitors. The key in this process is the change of the torsion angle between the P2 phenyl ring and the attached secondary amide by adding a small Cl, F, or Me group at the 2-position.