RESUMEN
Directed screening of nitrile compounds revealed 3 as a highly potent cathepsin K inhibitor but with cathepsin S activity and very poor stability to microsomes. Synthesis of compounds with reduced molecular complexity, such as 7, revealed key SAR and demonstrated that baseline physical properties and in vitro stability were in fact excellent for this series. The tricycle carboline P3 unit was discovered by hypothesis-based design using existing structural information. Optimization using small substituents, knowledge from matched molecular pairs, and control of lipophilicity yielded compounds very close to the desired profile, of which 34 (AZD4996) was selected on the basis of pharmacokinetic profile.
Asunto(s)
Carbolinas/farmacología , Catepsina K/antagonistas & inhibidores , Indoles/farmacología , Osteoartritis/tratamiento farmacológico , Inhibidores de Proteasas/farmacología , Animales , Carbolinas/metabolismo , Carbolinas/farmacocinética , Carbolinas/uso terapéutico , Catepsina K/química , Perros , Humanos , Indoles/metabolismo , Indoles/farmacocinética , Indoles/uso terapéutico , Concentración 50 Inhibidora , Masculino , Modelos Moleculares , Osteoartritis/enzimología , Inhibidores de Proteasas/metabolismo , Inhibidores de Proteasas/farmacocinética , Inhibidores de Proteasas/uso terapéutico , Conformación Proteica , Ratas , Especificidad por SustratoRESUMEN
A reliable method of automatically assigning one-dimensional proton spectra is described. The method relies on the alignment of the proton spectrum with an associated heteronuclear single-quantum coherence (HSQC) spectrum, transferring the stoichiometry and couplings to the HSQC. The HSQC spectrum is then assigned using a linear assignment procedure in which a fitness function incorporating (1)H chemical shifts, (1)H couplings and (13)C shifts are employed. The method uniquely employs a sequential procedure in which only correlations of like stoichiometry are assigned at the same time.