RESUMO
Modulation of cAMP levels has been linked to insulin secretion in preclinical animal models and in humans. The high expression of PDE-10A in pancreatic islets suggested that inhibition of this enzyme may provide the necessary modulation to elicit increased insulin secretion. Using an HTS approach, we have identified quinoline-based PDE-10A inhibitors as insulin secretagogues in vitro. Optimized compounds were evaluated in vivo where improvements in glucose tolerance and increases in insulin secretion were measured.
Assuntos
Insulina/metabolismo , Ilhotas Pancreáticas/efeitos dos fármacos , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/metabolismo , Quinolinas/farmacologia , Desenho de Fármacos , Humanos , Secreção de Insulina , Ilhotas Pancreáticas/metabolismo , Estrutura Molecular , Inibidores de Fosfodiesterase/síntese química , Diester Fosfórico Hidrolases/efeitos dos fármacos , Quinolinas/síntese química , Quinolinas/química , Relação Estrutura-AtividadeRESUMO
A series of indane acetic acid derivatives were prepared which show a spectrum of activity as insulin sensitizers and PPAR-alpha and PPAR-delta ligands. In vivo data are presented for insulin sensitizers with selectivity for PPAR-delta over PPAR-alpha.
Assuntos
Resistência à Insulina , PPAR delta/agonistas , Transferência Ressonante de Energia de Fluorescência , Relação Estrutura-AtividadeRESUMO
Novel anthranilamides were surprisingly found to exert additional activity on B-RAF. Corresponding thiophene, pyrazole, and thiazole core analogs were prepared as VEGFR-2 inhibitors with c-KIT, and B-RAF activity. Compounds in the phenyl, thiophene, and thiazole series are in vivo active.