RESUMO
A series of 5-phenyl-3-ureidobenzodiazepine-2,4-diones was synthesized and evaluated as cholecystokinin-B (CCK-B) receptor antagonists. Structure-activity relationship (SAR) studies revealed the importance of the N-1 substituent for potent and selective CCK-B affinity. Addition of substituents at the urea side chain provided in some cases more potent compounds. Moreover the introduction of bulky substituents such as adamantylmethyl at N-1 and resolution of the racemic ureas resulted in our lead compound GV150013.
Assuntos
Ansiolíticos/síntese química , Benzodiazepinas/síntese química , Receptores da Colecistocinina/antagonistas & inibidores , Animais , Ansiolíticos/química , Ansiolíticos/farmacologia , Benzodiazepinas/química , Benzodiazepinas/farmacologia , Callithrix , Córtex Cerebral/metabolismo , Cristalografia por Raios X , Cobaias , Células HeLa , Humanos , Técnicas In Vitro , Membranas , Camundongos , Modelos Moleculares , Pâncreas/metabolismo , Ensaio Radioligante , Ratos , Receptor de Colecistocinina A , Receptor de Colecistocinina B , Receptores da Colecistocinina/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Solid phase synthesis (SPS) is a powerful technique to assemble compound libraries in high-throughput parallel and combinatorial synthesis. The widespread applications of these techniques required the development of analytical methods for both structural elucidation and reaction monitoring. This review covers some recently developed techniques for on-bead analyses together with solution-state ones. Particular emphasis is devoted to software and hardware improvements for automated high-throughput analysis.