RESUMO
Analogues of the natural product noscapine were synthesized and their potential as antitumor agents evaluated. The discovery of a novel regioselective O-demethylation facilitated the synthesis of the potent aniline 6, which arrests mammalian cells in the G2/M phase of the cell cycle at 0.1 microM and also affects tubulin polymerization. Aniline 6 is orally bioavailable and is 250-fold more potent than noscapine in reducing cell proliferation in rapidly dividing cells.
Assuntos
Antineoplásicos/síntese química , Noscapina/análogos & derivados , Noscapina/síntese química , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Biopolímeros , Linhagem Celular , Ensaios de Seleção de Medicamentos Antitumorais , Fase G2/efeitos dos fármacos , Células HeLa , Humanos , Camundongos , Microtúbulos/efeitos dos fármacos , Noscapina/farmacocinética , Noscapina/farmacologia , Estereoisomerismo , Tubulina (Proteína)/química , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/químicaRESUMO
The 5-HT2C receptor has been implicated in the regulation of appetite. As such, small molecule agonists to this receptor may serve as novel therapies to combat obesity. We describe here the identification, synthesis, and SAR of a 5-HT2C agonist from a unique pyrimidine-diazabicyclo[3.3.0]octane series. This compound displayed good potency at the 5-HT2C receptor, modest selectivity relative to other 5-HT2 receptors, and was efficacious in an acute feeding study in rats.
Assuntos
Compostos Aza/química , Compostos Aza/farmacologia , Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Receptor 5-HT2C de Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina , Aminas/química , Animais , Compostos Aza/síntese química , Compostos Bicíclicos com Pontes/síntese química , Estrutura Molecular , Pirimidinas/síntese química , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
5-HT2C agonists have shown efficacy in limiting food consumption and thus may serve as an important drug class in combating obesity. We describe the design and synthesis of a novel tricyclic single-nitrogen scaffold that was used to produce 5-HT2C agonists. SAR was developed around this chemotype and compounds were identified that were potent (Ki<15 nM) and selective relative to other 5-HT2 receptors. The most promising compound displayed a good pharmacokinetic profile in multiple animal species, and was efficacious in an acute feeding study in rats.