Stachel Shawn J, Egbertson Melissa S, Wai Jenny, Machacek Michelle, Toolan Dawn M, Swestock John, Eddins Donnie M, Puri Vanita, McGaughey Georgia, Su Hua-Poo, Perlow Debbie, Wang Deping, Ma Lei, Parthasarathy Gopal, Reid John C, Abeywickrema Pravien D, Smith Sean M, Uslaner Jason M
Department of Medicinal Chemistry, Merck & Co. Inc., PO Box 4, West Point, PA 19486, USA.
Department of Medicinal Chemistry, Merck & Co. Inc., PO Box 4, West Point, PA 19486, USA.
Bioorg Med Chem Lett. 2018 Apr 1;28(6):1122-1126. doi: 10.1016/j.bmcl.2018.01.039. Epub 2018 Feb 10.
An internal HTS effort identified a novel PDE2 inhibitor series that was subsequently optimized for improved PDE2 activity and off-target selectivity. The optimized lead, compound 4, improved cognitive performance in a rodent novel object recognition task as well as a non-human primate object retrieval task. In addition, co-crystallization studies of close analog of 4 in the PDE2 active site revealed unique binding interactions influencing the high PDE isoform selectivity.
一项内部的高通量筛选工作确定了一个新型磷酸二酯酶2（PDE2）抑制剂系列，随后对其进行了优化，以提高PDE2活性和脱靶选择性。优化后的先导化合物4在啮齿动物的新物体识别任务以及非人类灵长类动物的物体检索任务中改善了认知表现。此外，对化合物4的紧密类似物在PDE2活性位点进行的共结晶研究揭示了影响高PDE同工型选择性的独特结合相互作用。
