MARK抑制剂：基于广泛的药物代谢动力学（DMPK）实验，对一个化学系列做出否定决定。
MARK inhibitors: Declaring a No-Go decision on a chemical series based on extensive DMPK experimentation.
作者信息
Haidle Andrew M, Childers Kaleen K, Zabierek Anna A, Katz Jason D, Jewell James P, Hou Yongquan, Altman Michael D, Szewczak Alexander, Chen Dapeng, Harsch Andreas, Hayashi Mansuo, Warren Lee, Hutton Michael, Nuthall Hugh, Stanton Matt G, Davies Ian W, Munoz Ben, Northrup Alan
机构信息
Department of Chemistry, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
Department of In Vitro Sciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
出版信息
Bioorg Med Chem Lett. 2017 Jan 1;27(1):109-113. doi: 10.1016/j.bmcl.2016.08.066. Epub 2016 Aug 25.
Attempts to optimize pharmacokinetic properties in a promising series of pyrrolopyrimidinone MARK inhibitors for the treatment of Alzheimer's disease are described. A focus on physical properties and ligand efficiency while prosecuting this series afforded key tool compounds that revealed a large discrepancy in the rat in vitro-in vivo DMPK (Drug Metabolism/Pharmacokinetics) correlation. These differences prompted an in vivo rat disposition study employing a radiolabeled representative of the series, and the results from this experiment justified the termination of any further optimization efforts.
本文描述了在一系列有前景的用于治疗阿尔茨海默病的吡咯并嘧啶酮MARK抑制剂中优化药代动力学性质的尝试。在推进该系列研究时，关注物理性质和配体效率得到了关键工具化合物，这些化合物揭示了大鼠体外-体内药物代谢/药代动力学（DMPK）相关性存在很大差异。这些差异促使开展一项使用该系列放射性标记代表物的大鼠体内处置研究，该实验结果证明应终止任何进一步的优化工作。
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