M1 PAM VU0453595的进一步优化：发现具有改善的中枢神经系统渗透性的新型杂双环核心基序。
Further optimization of the M1 PAM VU0453595: Discovery of novel heterobicyclic core motifs with improved CNS penetration.
作者信息
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
机构信息
Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, 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.
出版信息
Bioorg Med Chem Lett. 2016 Aug 1;26(15):3822-5. doi: 10.1016/j.bmcl.2016.04.083. Epub 2016 Apr 29.
Abstract
This Letter describes the continued chemical optimization of the VU0453595 series of M1 positive allosteric modulators (PAMs). By surveying alternative 5,6- and 6,6-heterobicylic cores for the 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one core of VU453595, we found new cores that engendered not only comparable or improved M1 PAM potency, but significantly improved CNS distribution (Kps 0.3-3.1). Moreover, this campaign provided fundamentally distinct M1 PAM chemotypes, greatly expanding the available structural diversity for this valuable CNS target, devoid of hydrogen-bond donors.
摘要
本信函描述了VU0453595系列M1正向变构调节剂（PAMs）的持续化学优化。通过研究VU453595的6,7-二氢-5H-吡咯并[3,4-b]吡啶-5-酮核心的替代5,6-和6,6-杂双环核心，我们发现了新的核心，这些核心不仅产生了相当或更高的M1 PAM效力，而且显著改善了中枢神经系统分布（脑渗透系数Kps为0.3 - 3.1）。此外，这项研究提供了根本不同的M1 PAM化学类型，极大地扩展了针对这个有价值的中枢神经系统靶点的可用结构多样性，且不含氢键供体。
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