Melancon Bruce J, Wood Michael R, Noetzel Meredith J, Nance Kellie D, Engelberg Eileen M, Han Changho, Lamsal Atin, Chang Sichen, Cho Hyekyung P, Byers Frank W, Bubser Michael, Jones Carrie K, Niswender Colleen M, Wood Michael W, Engers Darren W, Wu Dedong, Brandon Nicholas J, Duggan Mark E, Conn P Jeffrey, Bridges Thomas M, Lindsley Craig W
Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA.
Bioorg Med Chem Lett. 2017 Jun 1;27(11):2296-2301. doi: 10.1016/j.bmcl.2017.04.043. Epub 2017 Apr 13.
This letter describes the further chemical optimization of the 5-amino-thieno[2,3-c]pyridazine series (VU0467154/VU0467485) of M positive allosteric modulators (PAMs), developed via iterative parallel synthesis, culminating in the discovery of the non-human primate (NHP) in vivo tool compound, VU0476406 (8p). VU0476406 is an important in vivo tool compound to enable translation of pharmacodynamics from rodent to NHP, and while data related to a Parkinson's disease model has been reported with 8p, this is the first disclosure of the optimization and discovery of VU0476406, as well as detailed pharmacology and DMPK properties.
本信函描述了通过迭代平行合成开发的M型正变构调节剂（PAM）的5-氨基-噻吩并[2,3-c]哒嗪系列（VU0467154/VU0467485）的进一步化学优化，最终发现了非人类灵长类动物（NHP）体内工具化合物VU0476406（8p）。VU0476406是一种重要的体内工具化合物，可实现药效学从啮齿动物到NHP的转化，虽然已经报道了与帕金森病模型相关的8p数据，但这是VU0476406优化和发现以及详细药理学和药物代谢动力学性质的首次披露。
