RESUMO
A multi-disciplinary approach was used to identify the first pharmacophore model for KCC2 blockers: several physico-chemical studies such as XRD and NMR were combined to molecular modelling techniques, SAR analysis and synthesis of constrained analogues in order to determine a minimal conformational space regrouping few potential bioactive conformations. These conformations were further compared to the conformational space of a different series of KCC2 blockers in order to identify the common pharmacophoric features. The synthesis of more potent analogues in this second series confirmed the usefulness of this KCC2 blocker pharmacophore model.
Assuntos
Anticonvulsivantes/síntese química , Bloqueadores dos Canais de Potássio/síntese química , Prolina/análogos & derivados , Prolina/síntese química , Simportadores/antagonistas & inibidores , Animais , Anticonvulsivantes/farmacologia , Linhagem Celular Tumoral , Furosemida/farmacologia , Ensaios de Triagem em Larga Escala , Humanos , Transporte de Íons/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Conformação Molecular , Bloqueadores dos Canais de Potássio/farmacologia , Prolina/farmacologia , Ratos , Relação Estrutura-Atividade , Simportadores/metabolismo , Difração de Raios X , Cotransportadores de K e Cl-RESUMO
The discovery and optimization of a novel class of selective submicromolar KCC2 blockers is described. Details of synthesis and SAR are given together with ADME properties of selected compounds. A methylsulfone residue on the R(1) phenyl group improved the overall general profile of these prolinate derivatives.
Assuntos
Prolina/análogos & derivados , Simportadores/antagonistas & inibidores , Animais , Prolina/química , Prolina/farmacologia , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Cotransportadores de K e Cl-RESUMO
SAR around 4,6-diaminopyrimidine derivatives allowed the discovery of the first potent dual M(3) antagonists and PDE4 inhibitors. Various chemical modulations around that scaffold led to the discovery of ucb-101333-3 which is characterized by the most interesting profile on both targets.
