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Discovery and preclinical characterization of 1-methyl-3-(4-methylpyridin-3-yl)-6-(pyridin-2-ylmethoxy)-1H-pyrazolo-[3,4-b]pyrazine (PF470): a highly potent, selective, and efficacious metabotropic glutamate receptor 5 (mGluR5) negative allosteric modulator.发现并初步临床表征 1-甲基-3-(4-甲基吡啶-3-基)-6-(吡啶-2-基甲氧基)-1H-吡唑并-[3,4-b]吡嗪（PF470）：一种高效、选择性和有效的代谢型谷氨酸受体 5（mGluR5）负变构调节剂。
J Med Chem. 2014 Feb 13;57(3):861-77. doi: 10.1021/jm401622k. Epub 2014 Jan 22.
2
Discovery of VU0409106: A negative allosteric modulator of mGlu5 with activity in a mouse model of anxiety.VU0409106 的发现：一种 mGlu5 的负变构调节剂，在焦虑症小鼠模型中具有活性。
Bioorg Med Chem Lett. 2013 Nov 1;23(21):5779-85. doi: 10.1016/j.bmcl.2013.09.001. Epub 2013 Sep 10.
3
Substituted 1-Phenyl-3-(pyridin-2-yl)urea negative allosteric modulators of mGlu5: discovery of a new tool compound VU0463841 with activity in rat models of cocaine addiction.取代 1-苯基-3-(吡啶-2-基)脲 mGlu5 的负变构调节剂：具有可卡因成瘾大鼠模型中活性的新型工具化合物 VU0463841 的发现。
ACS Chem Neurosci. 2013 Aug 21;4(8):1217-28. doi: 10.1021/cn400070k. Epub 2013 May 29.
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mGlu5 negative allosteric modulators: a patent review (2010-2012).mGlu5 负变构调节剂：专利审查（2010-2012 年）。
Expert Opin Ther Pat. 2013 Apr;23(4):393-408. doi: 10.1517/13543776.2013.760544. Epub 2013 Jan 22.
5
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The effects of a novel metabotropic glutamate receptor 5 antagonist (AZD2066) on transient lower oesophageal sphincter relaxations and reflux episodes in healthy volunteers.新型代谢型谷氨酸受体 5 拮抗剂（AZD2066）对健康志愿者短暂性食管下括约肌松弛和反流事件的影响。
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Discovery of 2-(2-benzoxazoyl amino)-4-aryl-5-cyanopyrimidine as negative allosteric modulators (NAMs) of metabotropic glutamate receptor 5 (mGlu₅): from an artificial neural network virtual screen to an in vivo tool compound.2-(2-苯并恶唑基氨基)-4-芳基-5-氰基嘧啶作为代谢型谷氨酸受体5（mGlu₅）的负变构调节剂（NAMs）的发现：从人工神经网络虚拟筛选到体内工具化合物
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Functional impact of allosteric agonist activity of selective positive allosteric modulators of metabotropic glutamate receptor subtype 5 in regulating central nervous system function.选择性代谢型谷氨酸受体 5 别构激动剂对中枢神经系统功能的调节的变构激动剂活性的功能影响。
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(3-Cyano-5-fluorophenyl)biaryl negative allosteric modulators of mGlu(5): Discovery of a new tool compound with activity in the OSS mouse model of addiction.mGlu(5)的(3-氰基-5-氟苯基)联芳基负变构调节剂：在成瘾的OSS小鼠模型中发现一种具有活性的新型工具化合物。
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VU0431316的发现：一种mGlu5的负变构调节剂，在焦虑小鼠模型中具有活性。

Discovery of VU0431316: a negative allosteric modulator of mGlu5 with activity in a mouse model of anxiety.

作者信息

Bates Brittney S, Rodriguez Alice L, Felts Andrew S, Morrison Ryan D, Venable Daryl F, Blobaum Anna L, Byers Frank W, Lawson Kera P, Daniels J Scott, Niswender Colleen M, Jones Carrie K, Conn P Jeffrey, Lindsley Craig W, Emmitte Kyle A

机构信息

Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.

Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Tennessee Valley Healthcare System, U.S. Department of Veterans Affairs, Nashville, TN 37212, USA.

出版信息

Bioorg Med Chem Lett. 2014 Aug 1;24(15):3307-14. doi: 10.1016/j.bmcl.2014.06.003. Epub 2014 Jun 11.

DOI:10.1016/j.bmcl.2014.06.003
PMID:24969015
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4090943/
Abstract

Development of SAR in an aryl ether series of mGlu5 NAMs leading to the identification of pyrazine analog VU0431316 is described in this Letter. VU0431316 is a potent and selective non-competitive antagonist of mGlu5 that binds at a known allosteric binding site. VU0431316 demonstrates an attractive DMPK profile, including moderate clearance and good bioavailability in rats. Intraperitoneal (IP) dosing of VU0431316 in a mouse marble burying model of anxiety, an assay known to be sensitive to mGlu5 antagonists and other anxiolytics, produced dose proportional effects.

摘要

本信函描述了在一组芳基醚类代谢型谷氨酸受体5（mGlu5）负变构调节剂（NAM）中发现的构效关系，进而确定了吡嗪类似物VU0431316。VU0431316是一种强效且具有选择性的mGlu5非竞争性拮抗剂，可结合于已知的变构结合位点。VU0431316展现出良好的药物代谢动力学性质，包括在大鼠体内清除率适中且生物利用度良好。在小鼠大理石掩埋焦虑模型中腹腔注射VU0431316，该模型对mGlu5拮抗剂和其他抗焦虑药物敏感，结果显示其具有剂量依赖性效应。