RESUMO
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.
Assuntos
Catepsinas/antagonistas & inibidores , Nitrilas/química , Inibidores de Proteases/química , Pirimidinas/química , Sítios de Ligação , Catepsinas/metabolismo , Simulação por Computador , Humanos , Modelos Moleculares , Nitrilas/síntese química , Nitrilas/farmacologia , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologiaRESUMO
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.