Discovery and optimization of 3-(4-aryl/heteroarylsulfonyl)piperazin-1-yl)-6-(piperidin-1-yl)pyridazines as novel, CNS penetrant pan-muscarinic antagonists.
Discovery and optimization of 3-(4-aryl/heteroarylsulfonyl)piperazin-1-yl)-6-(piperidin-1-yl)pyridazines as novel, CNS penetrant pan-muscarinic antagonists.
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3-(4-芳基/杂芳基磺酰基)哌嗪-1-基)-6-(哌啶-1-基)哒嗪作为新型中枢神经系统渗透性全毒蕈碱拮抗剂的发现和优化。
DOI：
10.1016/j.bmcl.2017.05.042
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发表时间：
2017
影响因子：
2.7
通讯作者：
Lindsley,CraigW
中科院分区：
文献类型：
--
作者：
Bender,AaronM;Weiner,RebeccaL;Luscombe,VincentB;Ajmera,Sonia;Cho,HyekyungP;Chang,Sichen;Zhan,Xiaoyan;Rodriguez,AliceL;Niswender,ColleenM;Engers,DarrenW;Bridges,ThomasM;Conn,PJeffrey;Lindsley,CraigW
这封信描述了从高通量筛选活动中确定的基于3-(4-aryl/heteroarylsulfonyl)piperazin-1-yl)-6-(piperidin-1-yl)pyridazine核心的结构新颖的M4拮抗剂的合成和构效关系研究。多维优化努力增强了人类M4(HM4IC50s)的效力，仅注意到适度的物种差异，并具有对映选择性抑制。此外，中枢神经系统的穿透被证明对这个系列很有吸引力(大鼠脑：血浆Kp=22.1，Kp，UU=11.1)。尽管缺乏典型的mAChR拮抗剂碱性或季胺部分，但该系列在M1-5上显示出泛毒鼠碱拮抗剂活性(最多具有9至16倍的功能选择性)。这一系列进一步扩大了mAChR拮抗剂的化学多样性。
This letter describes the synthesis and structure activity relationship (SAR) studies of structurally novel M4antagonists, 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 M4(hM4IC50s < 200 nM), with only moderate species differences noted, and with enantioselective inhibition. Moreover, CNS penetration proved attractive for this series (rat brain:plasma Kp= 2.1, Kp,uu= 1.1). Despite the absence of the prototypical mAChR antagonist basic or quaternary amine moiety, this series displayed pan-muscarinic antagonist activity across M1-5(with 9- to 16-fold functional selectivity at best). This series further expands the chemical diversity of mAChR antagonists.