Janssen Research & Development, Medicinal Chemistry, Janssen-Cilag S.A., C/Jarama 75, 45007 Toledo, Spain.
Bioorg Med Chem Lett. 2013 Feb 1;23(3):785-90. doi: 10.1016/j.bmcl.2012.11.077. Epub 2012 Dec 1.
The synthesis, preliminary evaluation and structure-activity relationship (SAR) of a series of 1-aryl-4-methyl[1,2,4]triazolo[4,3-a]quinoxalines as dual phosphodiesterase 2/phosphodiesterase 10 (PDE2/PDE10) inhibitors are described. From this investigation compound 31 was identified, showing good combined potency, acceptable brain uptake and high selectivity for both PDE2 and PDE10 enzymes. Compound 31 was subjected to a microdosing experiment in rats, showing preferential distribution in brain areas where both PDE2 and PDE10 are highly expressed. These promising results may drive the further development of highly potent combined PDE2/PDE10 inhibitors, or even of selective inhibitors of PDE2 and/or PDE10.
本文描述了一系列 1-芳基-4-甲基[1,2,4]三唑并[4,3-a]喹喔啉作为双磷酸二酯酶 2/磷酸二酯酶 10（PDE2/PDE10）抑制剂的合成、初步评价和构效关系（SAR）。在这项研究中，鉴定出化合物 31，其具有良好的联合效力、可接受的脑摄取和对 PDE2 和 PDE10 酶的高选择性。化合物 31 在大鼠中进行了微量剂量实验，显示出在 PDE2 和 PDE10 高度表达的脑区的优先分布。这些有希望的结果可能会推动高活性的 PDE2/PDE10 双重抑制剂的进一步发展，甚至是 PDE2 和/或 PDE10 的选择性抑制剂的发展。
