Tarr James C, Wood Michael R, Noetzel Meredith J, Bertron Jeanette L, Weiner Rebecca L, Rodriguez Alice L, Lamsal Atin, Byers Frank W, Chang Sichen, Cho Hyekyung P, Jones Carrie K, Niswender Colleen M, Wood Michael W, Brandon Nicholas J, Duggan Mark E, Conn P Jeffrey, Bridges Thomas M, Lindsley Craig W
Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA.
Bioorg Med Chem Lett. 2017 Jul 1;27(13):2990-2995. doi: 10.1016/j.bmcl.2017.05.014. Epub 2017 May 6.
This letter details the continued chemical optimization of a novel series of M positive allosteric modulators (PAMs) based on a 5-amino-thieno[2,3-c]pyridazine core by incorporating a 3-amino azetidine amide moiety. The analogs described within this work represent the most potent M PAMs reported for this series to date. The SAR to address potency, clearance, subtype selectivity, CNS exposure, and P-gp efflux are described. This work culminated in the discovery of VU6000918, which demonstrated robust efficacy in a rat amphetamine-induced hyperlocomotion reversal model at a minimum efficacious dose of 0.3mg/kg.
这封信详细介绍了基于5-氨基噻吩并[2,3-c]哒嗪核心结构，通过引入3-氨基氮杂环丁烷酰胺部分对一系列新型M型正变构调节剂（PAMs）进行的持续化学优化。这项工作中描述的类似物是该系列迄今为止报道的最有效的M型PAMs。阐述了用于解决效力、清除率、亚型选择性、中枢神经系统暴露和P-糖蛋白外排的构效关系。这项工作最终发现了VU6000918，它在大鼠苯丙胺诱导的运动亢进逆转模型中，以最低有效剂量0.3mg/kg表现出强大的疗效。
