RESUMO
We describe the design, using shape comparison and fast docking computer algorithms, and rapid parallel synthesis of a 1300 member array based on GSK7721, a 4-aminobenzonitrile androgen receptor (AR) antagonist identified by focused screening of the GSK compound collection. The array yielded 352 submicromolar and 17 subnanomolar AR agonists as measured by a cell-based reporter gene functional assay. The rapid synthesis of a large number of active compounds provided valuable information in the optimization of AR modulators, which may be useful in treating androgen deficiency in aging males.
Assuntos
Antagonistas de Receptores de Andrógenos , Técnicas de Química Combinatória/métodos , Nitrilas/síntese química , Nitrilas/farmacologia , Algoritmos , Androgênios , Animais , Linhagem Celular , Desenho de Fármacos , Haplorrinos , Espectroscopia de Ressonância Magnética , Nitrilas/química , Espectrometria de Massas de Bombardeamento Rápido de Átomos , Relação Estrutura-AtividadeRESUMO
Traditional approaches to discovery of selective estrogen receptor modulators (SERMs) have relied on ER binding and cell-based estrogen response element-driven assays to identify compounds that are osteoprotective but nonproliferative in breast and uterine tissues. To discover new classes of potential SERMs, we have employed a cell-free microsphere-based binding assay to rapidly characterize ERalpha interactions with conformation-sensing cofactor or phage display peptides. Peptide profiles of constrained triarenes were compared to known proliferative and nonproliferative ER ligands to discover potent quinoline-based ligands with minimal Ishikawa cell stimulation.