RESUMO
N1-Arylsulfonyltryptamines have been identified as 5-HT6 receptor ligands. In particular, N1-(6-chloroimidazo[2,1-b][1,3]thiazole-5-sulfonyl)tryptamine (11q) is a high affinity, potent full agonist (5-HT6 Ki = 2 nM, EC50 = 6.5 nM, Emax = 95.5%). Compound 11q is selective in a panel of over 40 receptors and ion channels, has good pharmacokinetic profile, has been shown to increase GABA levels in the rat frontal cortex, and is active in the schedule-induced polydipsia model for obsessive compulsive disorders.
Assuntos
Receptores de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/síntese química , Tiazóis/química , Triptaminas/síntese química , Administração Oral , Animais , Disponibilidade Biológica , Células CHO , Cricetinae , Cricetulus , Cães , Lobo Frontal/metabolismo , Haplorrinos , Humanos , Técnicas In Vitro , Camundongos , Microdiálise , Microssomos Hepáticos/metabolismo , Ensaio Radioligante , Ratos , Agonistas do Receptor de Serotonina/farmacocinética , Agonistas do Receptor de Serotonina/farmacologia , Solubilidade , Relação Estrutura-Atividade , Tiazóis/farmacocinética , Tiazóis/farmacologia , Triptaminas/química , Triptaminas/farmacocinética , Triptaminas/farmacologia , Ácido gama-Aminobutírico/metabolismoRESUMO
SAR on HTS hits 1 and 2 led to the potent, Notch-1-sparing GSI 9, which lowered brain Abeta in Tg2576 mice at 100 mg/kg po. Converting the metabolically labile methyl groups in 9 to trifluoromethyl groups afforded the more stable analogue 10, which had improved in vivo potency. Further side chain modification afforded the potent Notch-1-sparing GSI begacestat (5), which was selected for development for the treatment of Alzheimer's disease.