Ernst Glen, Akuma Daniel, Au Vinh, Buchler Ingrid P, Byers Spencer, Carr Gregory V, Defays Sabine, de León Pablo, Demaude Thierry, DePasquale Michael, Durieu Véronique, Huang Yifang, Jigorel Emilie, Kimos Martha, Kolobova Anna, Montel Florian, Moureau Florence, Poslusney Michael, Swinnen Dominique, Vandergeten Marie-Christine, Van Houtvin Nathalie, Wei Huijun, White Noelle, Wood Martyn, Barrow James C
Lieber Institute for Brain Development, 855 North Wolfe Street, Baltimore, Maryland 21205, United States.
Department of Pharmacology, Johns Hopkins University School of Medicine, 855 North Wolfe Street, Baltimore, Maryland 21287, United States.
ACS Med Chem Lett. 2019 Oct 22;10(11):1573-1578. doi: 10.1021/acsmedchemlett.9b00345. eCollection 2019 Nov 14.
A series of bicyclic pyridones were identified as potent inhibitors of catechol -methyltransferase (COMT). Substituted benzyl groups attached to the basic nitrogen of the core scaffold gave the most potent inhibitors within this series. Rat pharmacokinetic studies showed medium to high levels of clearance for this series, but with high free fraction due to remarkably low levels of protein and tissue binding. In rat biomarker studies, levels of unbound drug exposure are seen in the brain, which exceed their respective ICs, leading to changes in the levels of dopamine metabolites in a manner consistent with COMT inhibition.
一系列双环吡啶酮被鉴定为儿茶酚 - 甲基转移酶（COMT）的强效抑制剂。连接在核心骨架碱性氮上的取代苄基产生了该系列中最有效的抑制剂。大鼠药代动力学研究表明，该系列药物的清除率处于中等至高水平，但由于蛋白质和组织结合水平极低，游离分数较高。在大鼠生物标志物研究中，大脑中可见未结合药物暴露水平超过其各自的IC值，导致多巴胺代谢物水平以与COMT抑制一致的方式发生变化。
