RESUMO
High throughput screening led to the discovery of a novel series of 1,3-diaminopropan-2-ol sulfonamides as selective GlyT-1 inhibitors. Structure-activity relationships of this novel series and optimisation of the initial hit that led to the identification of (2), a potent and selective GlyT-1 inhibitor, are also presented.
Assuntos
Proteínas da Membrana Plasmática de Transporte de Glicina/antagonistas & inibidores , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Animais , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão , Simulação por Computador , Avaliação Pré-Clínica de Medicamentos , Humanos , Isomerismo , Conformação Molecular , Ratos , Espectrofotometria Ultravioleta , Relação Estrutura-AtividadeRESUMO
Intramolecular 6-exolendo-trig and 5-exo-trig cyclisations of aryl radical intermediates to the alpha-, beta- and gamma-carbons of pyridine have been shown to be facile processes at neutral pH. The tether conjoining the radical donor to the pyridine plays an important role in determining the outcome of the reaction. When a Z-alkene is used as a tether, ortho-cyclisation proceeds in good yield. A more complex course is followed when a saturated two carbon tether is employed, leading to products derived from hydrogen atom abstraction, ipso-cyclisation and ortho-cyclisation pathways. All attempts to effect 5-exolendo-trig cyclisations failed. Tributyltin hydride, tris(trimethylsilyl)silane, tris(trimethylsilyl)germane and, in part, samarium(II) iodide can each be employed as mediators of the reaction.