Elger Bernd, Schneider Matthias, Winter Eric, Carvelli Lucia, Bonomi Marco, Fracasso Claudia, Guiso Giovanna, Colovic Milena, Caccia Silvio, Mennini Tiziana
Schering AG, Muellerstrasse 178, Berlin, Germany.
ChemMedChem. 2006 Oct;1(10):1142-8. doi: 10.1002/cmdc.200600144.
Previous structure-activity relationship studies in the search for a potent, noncompetitive alpha-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor antagonist led to 2,3-dimethyl-6-phenyl-12H-[1,3]dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine (ZK 187638). However, the first synthesis had some drawbacks regarding reagents, processes, and overall yield, which furthermore decreased when the synthesis was scaled up. Therefore, we now report a new synthetic route for this compound which requires fewer steps and is suited for large-scale production. This compound significantly relieved the symptoms of neuromuscular deficit in mnd mice, a model of neuronal ceroid lipofuscinosis with motor neuron dysfunction. After oral administration, the concentrations of the compound in the brain and spinal cord were about threefold higher than those in the plasma. In summary, this novel AMPA antagonist is accessible through an optimized synthetic route, has good neurobehavioral activity, oral bioavailability, and favorable brain penetration. This opens new possibilities for the treatment of devastating neurological diseases that are mediated by the AMPA receptor.
先前在寻找一种强效、非竞争性α-氨基-3-(3-羟基-5-甲基-4-异恶唑基)丙酸(AMPA)受体拮抗剂的构效关系研究中，得到了2,3-二甲基-6-苯基-12H-[1,3]二氧杂环戊烯并[4,5-h]咪唑并[1,2-c][2,3]苯并二氮杂卓(ZK 187638)。然而，首次合成在试剂、工艺和总产率方面存在一些缺点，而且在扩大规模合成时这些缺点进一步加剧。因此，我们现在报道一种该化合物的新合成路线，该路线步骤更少，适合大规模生产。该化合物显著缓解了运动神经元功能障碍的神经元蜡样脂褐质沉积症模型(mnd小鼠)的神经肌肉缺陷症状。口服给药后，该化合物在脑和脊髓中的浓度比在血浆中的浓度高约三倍。总之，这种新型AMPA拮抗剂可通过优化的合成路线获得，具有良好的神经行为活性、口服生物利用度和良好的脑渗透性。这为治疗由AMPA受体介导的毁灭性神经疾病开辟了新的可能性。
