Tarr James C, Wood Michael R, Noetzel Meredith J, Melancon Bruce J, Lamsal Atin, Luscombe Vincent B, Rodriguez Alice L, Byers Frank W, Chang Sichen, Cho Hyekyung P, Engers Darren W, 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 Dec 1;27(23):5179-5184. doi: 10.1016/j.bmcl.2017.10.053. Epub 2017 Oct 24.
Herein we describe the continued optimization of M positive allosteric modulators (PAMs) within the 5-amino-thieno[2,3-c]pyridazine series of compounds. In this letter, we disclose our studies on tertiary amides derived from substituted azetidines. This series provided excellent CNS penetration, which had been challenging to consistently achieve in other amide series. Efforts to mitigate high clearance, aided by metabolic softspot analysis, were unsuccessful and precluded this series from further consideration as a preclinical candidate. In the course of this study, we found that potassium tetrafluoroborate salts could be engaged in a tosyl hydrazone reductive cross coupling reaction, a previously unreported transformation, which expands the synthetic utility of the methodology.
在此，我们描述了5-氨基噻吩并[2,3-c]哒嗪系列化合物中M阳性变构调节剂（PAMs）的持续优化。在这封信中，我们披露了对源自取代氮杂环丁烷的叔酰胺的研究。该系列具有出色的中枢神经系统渗透性，而在其他酰胺系列中一直难以持续实现这一点。借助代谢软点分析减轻高清除率的努力未成功，因此该系列不再作为临床前候选药物进一步考虑。在本研究过程中，我们发现四氟硼酸钾盐可参与甲苯磺酰腙还原交叉偶联反应，这是一种以前未报道的转化反应，扩展了该方法的合成应用。
