吡啶并[4,3-e][1,2,4]三唑并[4,3-a]吡嗪类化合物作为选择性、可穿透血脑屏障的磷酸二酯酶2（PDE2）抑制剂。
Pyrido[4,3-e][1,2,4]triazolo[4,3-a]pyrazines as Selective, Brain Penetrant Phosphodiesterase 2 (PDE2) Inhibitors.
作者信息
Rombouts Frederik J R, Tresadern Gary, Buijnsters Peter, Langlois Xavier, Tovar Fulgencio, Steinbrecher Thomas B, Vanhoof Greet, Somers Marijke, Andrés José-Ignacio, Trabanco Andrés A
机构信息
Neuroscience-Medicinal Chemistry, Discovery Sciences, Neuroscience-Biology, Janssen Research & Development, Janssen Pharmaceutica N.V. , Turnhoutseweg 30, B-2340 Beerse, Belgium.
Villapharma Research S.L., Parque Tecnológico de Fuente Álamo. Ctra. El Estrecho-Lobosillo , Km. 2,5- Av. Azul, 30320 Fuente Álamo de Murcia, Murcia, Spain.
出版信息
ACS Med Chem Lett. 2015 Jan 15;6(3):282-6. doi: 10.1021/ml500463t. eCollection 2015 Mar 12.
Abstract
A novel series of pyrido[4,3-e][1,2,4]triazolo[4,3-a]pyrazines is reported as potent PDE2/PDE10 inhibitors with drug-like properties. Selectivity for PDE2 was obtained by introducing a linear, lipophilic moiety on the meta-position of the phenyl ring pending from the triazole. The SAR and protein flexibility were explored with free energy perturbation calculations. Rat pharmacokinetic data and in vivo receptor occupancy data are given for two representative compounds 6 and 12.
摘要
据报道，一系列新型的吡啶并[4,3-e][1,2,4]三唑并[4,3-a]吡嗪是具有类药物性质的强效PDE2/PDE10抑制剂。通过在连接于三唑的苯环间位引入一个线性亲脂性部分，获得了对PDE2的选择性。利用自由能微扰计算探索了构效关系和蛋白质柔性。给出了两种代表性化合物6和12的大鼠药代动力学数据和体内受体占有率数据。
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