RESUMO
We have synthesized and evaluated a series of triaryl sulfonamide-based PTP1B inhibitors in which a difluoro-methylenephosphonate group of a potent lead has been replaced by potential bioisosteric replacements. Several mono- or di-charged compounds (8a, 8b, and 15a) were shown exhibit inhibitory activity in the low micromolar range, demonstrating the feasibility of using this approach in identifying non-phosphonate pTyr mimetics in a small molecular scaffold. These results also provide a useful indication of the relative effectiveness of these pTyr mimetics.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Compostos de Flúor/síntese química , Compostos Organofosforados/síntese química , Compostos Organofosforados/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Sulfonamidas/química , Inibidores Enzimáticos/química , Compostos de Flúor/química , Compostos de Flúor/farmacologia , Estrutura Molecular , Compostos Organofosforados/química , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Relação Estrutura-AtividadeRESUMO
A series of novel sulfonamides containing a single difluoromethylene-phosphonate group were discovered to be potent inhibitors of protein tyrosine phosphatase 1B. Structure-activity relationships around the scaffold were investigated, leading to the identification of compounds with IC50 or Ki values in the low nanomolar range. These sulfonamide-based inhibitors exhibit 100 and 30 times higher inhibitory activity than the corresponding tertiary amines and carboxamides, respectively.
