RESUMO
Restoration of p53 activity by inhibition of the p53-MDM2 interaction has been considered an attractive approach for cancer treatment. However, the hydrophobic protein-protein interaction surface represents a significant challenge for the development of small-molecule inhibitors with desirable pharmacological profiles. RG7112 was the first small-molecule p53-MDM2 inhibitor in clinical development. Here, we report the discovery and characterization of a second generation clinical MDM2 inhibitor, RG7388, with superior potency and selectivity.
Assuntos
Antineoplásicos/síntese química , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Pirrolidinas/síntese química , Proteína Supressora de Tumor p53/antagonistas & inibidores , para-Aminobenzoatos/síntese química , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Descoberta de Drogas , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pirrolidinas/farmacologia , Pirrolidinas/uso terapêutico , para-Aminobenzoatos/farmacologia , para-Aminobenzoatos/uso terapêuticoRESUMO
A concise synthesis of the beta-amyloid(1-42 )aggregation inhibitor (-)-5,8-dihydroxy-3R-methyl-2R-(dipropylamino)-1,2,3,4-tetrahydronaphthalene [(-)-2] has been developed. The key step is a regio- and diastereoselective hydroboration-amination sequence to convert alkene into amine. Enantiomeric resolution was achieved by recrystallization of amine as the dibenzoyl-D-tartaric acid salt. Hydroquinone is a potent inhibitor of the fibrillar aggregation of beta-amyloid as determined in two different assay systems.
