Further optimization of the M-1 PAM VU0453595: Discovery of novel heterobicyclic core motifs with improved CNS penetration

Panarese Joseph D.; Cho Hykeyung P.; Adams Jeffrey J.; Nance Kellie D.; Garcia-Barrantes Pedro M.; Chang Sichen; Morrison Ryan D.; Blobaum Anna L.; Niswender Colleen M.; Stauffer Shaun R.; Conn P. Jeffrey; Lindsley Craig W.

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Further optimization of the M-1 PAM VU0453595: Discovery of novel heterobicyclic core motifs with improved CNS penetration

机译：M-1 PAM的进一步优化VU0453595：发现具有改进的CNS渗透性的新型杂环双环核心基序

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This Letter describes the continued chemical optimization of the VU0453595 series of M-1 positive allosteric modulators (PAMs). By surveying alternative 5,6- and 6,6-heterobicylic cores for the 6,7-dihy-dro-5H-pyrrolo[3,4-b]pyridine-5-one core of VU453595, we found new cores that engendered not only comparable or improved M-1 PAM potency, but significantly improved CNS distribution (K(p)s 0.3-3.1). Moreover, this campaign provided fundamentally distinct M-1 PAM chemotypes, greatly expanding the available structural diversity for this valuable CNS target, devoid of hydrogen-bond donors. (C) 2016 Elsevier Ltd. All rights reserved.

机译：该信函描述了VU0453595系列M-1阳性变构调节剂（PAM）的持续化学优化。通过调查VU453595的6,7-二氢-dro-5H-吡咯并[3,4-b]吡啶-5核的替代5,6-和6,6-异核核，我们发现没有产生的新核仅可比或改善M-1 PAM效能，但显着改善CNS分布（K（p）s 0.3-3.1）。此外，这项运动从根本上提供了独特的M-1 PAM化学型，极大地扩展了这一宝贵的中枢神经系统靶标的可用结构多样性，而没有氢键供体。（C）2016 Elsevier Ltd.保留所有权利。

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《Bioorganic and Medicinal Chemistry Letters》 |2016年第15期|共4页
作者
Panarese Joseph D.; Cho Hykeyung P.; Adams Jeffrey J.; Nance Kellie D.; Garcia-Barrantes Pedro M.; Chang Sichen; Morrison Ryan D.; Blobaum Anna L.; Niswender Colleen M.; Stauffer Shaun R.; Conn P. Jeffrey; Lindsley Craig W.;
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M-1; Muscarinic acetylcholine receptor; Positive allosteric modulator (PAM); CNS penetration; Structure-activity relationship (SAR);

机译：M-1;毒蕈碱型乙酰胆碱受体;正变构调节剂（PAM）;CNS穿透;构效关系（SAR）;

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专利

1. Further optimization of the M-1 PAM VU0453595: Discovery of novel heterobicyclic core motifs with improved CNS penetration [J] . Panarese Joseph D., Cho Hykeyung P., Adams Jeffrey J., Bioorganic and Medicinal Chemistry Letters . 2016,第15期

机译：M-1 PAM的进一步优化VU0453595：发现具有改进的CNS渗透性的新型杂环双环核心基序
2. Re-exploration of the mGlu(1) PAM Ro 07-11401 scaffold: Discovery of analogs with improved CNS penetration despite steep SAR [J] . Garcia-Barrantes Pedro M., Cho Hyekyung P., Starr Tahj M., Bioorganic and Medicinal Chemistry Letters . 2016,第9期

机译：mGlu（1）PAM Ro 07-11401支架的再探索：尽管SAR陡峭，但发现具有改善的CNS渗透性的类似物
3. Discovery and optimization of a novel series of highly CNS penetrant M-4 PAMs based on a 5,6-dimethyl-4-(piperidin-1-yl)thieno[2,3-d]pyrimidine core [J] . Wood Michael R., Noetzel Meredith J., Engers Julie L., Bioorganic and Medicinal Chemistry Letters . 2016,第13期

机译：基于5,6-二甲基-4-（哌啶-1-基）噻吩并[2,3-d]嘧啶核的新型高CNS渗透性M-4 PAM系列的发现和优化
4. Efficient Computation of Motif Discovery on Intel Many Integrated Core (MIC) Architecture [C] . Kaiwen Huang, Zhiqiang Zhang, Runxin Guo, International symposium on bioinformatics research and applications . 2017

机译：英特尔多核集成（MIC）架构上Motif Discovery的高效计算
5. Integrating systems biology data repositories to improve cis-regulatory motif characterization and discovery: An elegant solution to an old difficult problem. [D] . Quest, Daniel J. 2009

机译：集成系统生物学数据存储库以改善顺式调控基序的表征和发现：一种解决老难题的绝妙方法。
6. Further optimization of the M1 PAM VU0453595: Discovery of novel heterobicyclic core motifs with improved CNS penetration [O] . Joseph D. Panarese, Hykeyung P. Cho, Jeffrey J. Adams, -1

机译：M1 PAM的进一步优化VU0453595：发现具有改进的CNS穿透性的新型杂环双环基序
7. Continued optimization of the M 5 NAM ML375: Discovery of VU6008667, an M 5 NAM with high CNS penetration and a desired short half-life in rat for addiction studies [O] . Kevin M. McGowan, Kellie D. Nance, Hykeyung P. Cho, 2017

机译：持续优化M 5 NAM ML375：VU6008667的发现，一个高CNS渗透和大鼠中所需的短半衰期，对成瘾研究
8. BWR Improved Refueling Patterns; Reduction in Gadolinia Residual; Axial-Blanket Optimization; Improved Initial-Core Design [R] . Hopkins, G. C. 1981

机译：BWR改进加油模式;减少Gadolinia残留;轴向毯优化;改进的初始核心设计

Further optimization of the M-1 PAM VU0453595: Discovery of novel heterobicyclic core motifs with improved CNS penetration

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