发现并优化一种新型、选择性和可穿透血脑屏障的 M1 正变构调节剂 (PAM)：MLPCN 探针 ML169 的研发。
Discovery and optimization of a novel, selective and brain penetrant M1 positive allosteric modulator (PAM): the development of ML169, an MLPCN probe.
机构信息
Vanderbilt Institute of Chemical Biology/Chemical Synthesis Core, Nashville, TN 37232, USA.
出版信息
Bioorg Med Chem Lett. 2011 May 1;21(9):2697-701. doi: 10.1016/j.bmcl.2010.12.015. Epub 2010 Dec 9.
Abstract
This Letter describes a chemical lead optimization campaign directed at VU0108370, a weak M(1) PAM hit with a novel chemical scaffold from a functional HTS screen within the MLPCN. An iterative parallel synthesis approach rapidly established SAR for this series and afforded VU0405652 (ML169), a potent, selective and brain penetrant M(1) PAM with an in vitro profile comparable to the prototypical M(1) PAM, BQCA, but with an improved brain to plasma ratio.
摘要
这封信描述了一项针对 VU0108370 的化学先导优化活动，VU0108370 是一种来自 MLPCN 内功能性高通量筛选的新型化学支架的弱 M(1) PAM 命中物。一种迭代平行合成方法迅速确定了该系列的 SAR，并获得了 VU0405652（ML169），这是一种有效的、选择性的和穿透大脑的 M(1) PAM，具有与原型 M(1) PAM，BQCA 相当的体外特征，但具有改善的脑到血浆比。
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