RESUMO
A series of 3-imino-2-indolones are the first published, high-affinity antagonists of the galanin GAL3 receptor. One example, 1,3-dihydro-1-phenyl-3-[[3-(trifluoromethyl)phenyl]imino]-2H-indol-2-one (9), was shown to have high affinity for the human GAL3 receptor (Ki=17 nM) and to be highly selective for GAL3 over a broad panel of targets, including GAL1 and GAL2. Compound 9 was also shown to be an antagonist in a human GAL3 receptor functional assay (Kb=29 nM).
Assuntos
Iminas/síntese química , Indóis/síntese química , Receptor Tipo 3 de Galanina/antagonistas & inibidores , Animais , Ligação Competitiva , Encéfalo/metabolismo , Células COS , Chlorocebus aethiops , AMP Cíclico/biossíntese , Humanos , Iminas/farmacocinética , Iminas/farmacologia , Indóis/farmacocinética , Indóis/farmacologia , Ligantes , Ensaio Radioligante , Ratos , Receptor Tipo 1 de Galanina/efeitos dos fármacos , Receptor Tipo 2 de Galanina/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A benzylpiperidine analogue with an acetylenic linker, 5-(3-[4-(4-fluorobenzyl)-piperidin-1-yl]-prop-1-ynyl)-1,3-dihydrobenzimidazol-2-one (3), was identified as a chemical lead with excellent activity at the NR1A/2B receptor (IC50=3 nM). Efforts to optimize this activity led to focused modifications around the structural motif of 3. The synthesis and SAR studies are discussed.
