RESUMEN
A series of tetrahydropyrido-pyrazole cathepsin S (CatS) inhibitors with thioether acetamide functional groups were prepared with the goal of improving upon the cellular activity of amidoethylthioethers. This Letter describes altered amide connectivity, in conjunction with changes to other binding elements, resulting in improved potency, as well as increased knowledge of the relationship between this chemotype and human CatS activity.
Asunto(s)
Acetamidas/farmacología , Catepsinas/antagonistas & inhibidores , Catepsinas/metabolismo , Inhibidores de Proteasas/farmacología , Pirazoles/farmacología , Sulfuros/farmacología , Acetamidas/química , Catepsinas/química , Línea Celular , Humanos , Modelos Moleculares , Inhibidores de Proteasas/química , Pirazoles/química , Relación Estructura-Actividad , Sulfuros/químicaRESUMEN
A novel class of tetrahydropyrido-pyrazole thioether amines that display potency against human Cathepsin S have been previously reported. Here, further SAR investigations of the P3, P4, and P5 regions are described. In particular, 4-fluoropiperidine is identified as a competent P3 binding element when utilized in conjunction with a (S)-2-hydroxypropyl linker-containing P5 moiety and oxamide or sulfonamide P4 substitution.
Asunto(s)
Catepsinas/antagonistas & inhibidores , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Pirazoles/química , Pirazoles/farmacología , Sulfuros/química , Sulfuros/farmacología , Catepsinas/metabolismo , Línea Celular , Humanos , Relación Estructura-ActividadRESUMEN
A series of pyrazole-based thioethers were prepared and found to be potent cathepsin S inhibitors. A crystal structure of 13 suggests that the thioether moiety may bind to the S3 pocket of the enzyme. Additional optimization led to the discovery of aminoethylthioethers with improved enzymatic activity and submicromolar cellular potency.
Asunto(s)
Catepsinas/antagonistas & inhibidores , Catepsinas/metabolismo , Inhibidores de Proteasas/farmacología , Pirazoles/farmacología , Sulfuros/farmacología , Sitios de Unión , Catepsinas/química , Línea Celular , Cristalografía por Rayos X , Humanos , Modelos Moleculares , Inhibidores de Proteasas/química , Pirazoles/química , Relación Estructura-Actividad , Sulfuros/químicaRESUMEN
INTRODUCTION: Cathepsin S, a lysosomal cysteine protease, plays an important role in antigen presentation. Its inhibition is expected to result in immunosuppression, making this enzyme an attractive target to potentially treat autoimmune and inflammatory diseases. AREAS COVERED: The focus of this review is on patent literature regarding small molecule inhibitors of cathepsin S published from 2004 to April 2010. Different structure classes based on binding strategies (covalent vs non-covalent) are surveyed and listed according to warhead type and research organization. EXPERT OPINION: Although > 40 patent applications have appeared between 2004 and 2010, the decrease in applications focusing on cathepsin S over the past 2 - 3 years may reflect a renewed interest in other cathepsins, especially cathepsin K, for which a small molecule inhibitor is currently in Phase III clinical trials.