基于乙基-8-甲氧基-4-(4-苯哌嗪-1-基)喹啉羧酸酯核心的一系列 mGluNAMs 的合成及 SAR 研究。
Synthesis and SAR of a series of mGlu NAMs based on an ethyl-8-methoxy-4-(4-phenylpiperazin-1-yl)quinoline carboxylate core.
机构信息
Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA.
Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
出版信息
Bioorg Med Chem Lett. 2020 Nov 15;30(22):127529. doi: 10.1016/j.bmcl.2020.127529. Epub 2020 Sep 2.
A High-Throughput Screening (HTS) campaign identified a fundamentally new mGlu NAM chemotype, based on an ethyl-8-methoxy-4-(4-phenylpiperazin-1-yl)quinolone carboxylate core. The initial hit, VU0226390, was a potent mGlu NAM (IC = 647 nM, 6% L-AP4 min) with selectivity versus the other group III mGlu receptors (>30 μM vs. mGlu and mGlu). A multi-dimensional optimization effort surveyed all regions of this new chemotype, and found very steep SAR, reminiscent of allosteric modulators, and unexpected piperazine mimetics (whereas classical bioisosteres failed). While mGlu NAM potency could be improved (ICs ~ 350 nM), the necessity of the ethyl ester moiety and poor physiochemical and DMPK properties precluded optimization towards in vivo tool compounds or clinical candidates. Still, this hit-to-lead campaign afforded key medicinal chemistry insights and new opportunities.
高通量筛选（HTS）活动基于乙基-8-甲氧基-4-（4-苯基哌嗪-1-基）喹啉羧酸酯核心，发现了一种全新的 mGluNAM 化学型。最初的命中化合物 VU0226390 是一种有效的 mGluNAM（IC=647 nM，6% L-AP4 min），对其他组 III mGlu 受体具有选择性（>30 μM 对 mGlu 和 mGlu）。多维优化工作调查了该新型化学型的所有区域，并发现了非常陡峭的 SAR，类似于变构调节剂，以及意想不到的哌嗪类似物（而经典的生物等排体则失败了）。虽然 mGluNAM 的效力可以提高（ICs~350 nM），但乙基酯部分的必要性以及较差的理化和 DMPK 性质排除了向体内工具化合物或临床候选物进行优化的可能性。尽管如此，这次从命中化合物到先导化合物的研究活动提供了关键的药物化学见解和新的机会。
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