Bender Aaron M, Weiner Rebecca L, Luscombe Vincent B, Ajmera Sonia, Cho Hyekyung P, Chang Sichen, Zhan Xiaoyan, Rodriguez Alice L, Niswender Colleen M, Engers Darren W, Bridges Thomas M, Conn P Jeffrey, Lindsley Craig W
Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Pharmacology, 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 Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Bioorg Med Chem Lett. 2017 Aug 1;27(15):3576-3581. doi: 10.1016/j.bmcl.2017.05.042. Epub 2017 May 15.
This letter describes the synthesis and structure activity relationship (SAR) studies of structurally novel M antagonists, based on a 3-(4-aryl/heteroarylsulfonyl)piperazin-1-yl)-6-(piperidin-1-yl)pyridazine core, identified from a high-throughput screening campaign. A multi-dimensional optimization effort enhanced potency at human M (hM ICs<200nM), with only moderate species differences noted, and with enantioselective inhibition. Moreover, CNS penetration proved attractive for this series (rat brain:plasma K=2.1, K=1.1). Despite the absence of the prototypical mAChR antagonist basic or quaternary amine moiety, this series displayed pan-muscarinic antagonist activity across M (with 9- to 16-fold functional selectivity at best). This series further expands the chemical diversity of mAChR antagonists.
这封信描述了基于从高通量筛选活动中鉴定出的3-(4-芳基/杂芳基磺酰基)哌嗪-1-基)-6-(哌啶-1-基)哒嗪核心结构新颖的M拮抗剂的合成及构效关系(SAR)研究。通过多维度优化，提高了对人M的效力(hM IC50<200nM)，仅观察到适度的种属差异，且具有对映选择性抑制。此外，该系列化合物的中枢神经系统渗透性被证明具有吸引力(大鼠脑:血浆Kp=2.1，Kpu=1.1)。尽管没有典型的毒蕈碱型乙酰胆碱受体拮抗剂的碱性或季胺部分，但该系列在M1-M5上均表现出泛毒蕈碱拮抗剂活性(最佳情况下具有9至−16倍的功能选择性)。该系列进一步扩展了毒蕈碱型乙酰胆碱受体拮抗剂的化学多样性。
