Design of 4-Oxo-1-aryl-1,4-dihydroquinoline-3-carboxamides as Selective Negative Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 2
Design of 4-Oxo-1-aryl-1,4-dihydroquinoline-3-carboxamides as Selective Negative Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 2
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DOI：
10.1021/acs.jmedchem.5b01371
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发表时间：
2015-11-26
影响因子：
7.3
通讯作者：
Emmitte, Kyle A.
中科院分区：
文献类型：
--
作者：
Felts, Andrew S.;Rodriguez, Alice L.;Emmitte, Kyle A.
第二类代谢性谷氨酸受体(MGlus)的正构和变构拮抗剂已被用来建立mGlu(2/3)抑制与多种中枢神经系统疾病和障碍之间的联系。虽然这些工具通常对mGlu(2/3)比mGlu家族的其余六个成员具有良好的选择性，但事实证明，仅对单个II族mGlu中的一个具有选择性的化合物难以捉摸。在此，我们报道了从一系列4-oxo-1-aryl-1，4-dihydroquinoline-3-carboxamides.中发现了一种有效的和高选择性的mGlu2负变构调节剂58(VU6001192)这一系列的设计理念集中在将最近在专利文献中公开的喹啉系列转变为以前用于制备M碱乙酰胆碱受体亚型1正变构调节剂的化合型。化合物58显示出良好的轮廓，并将是一个有用的工具，以了解在中枢神经系统中选择性抑制mGlu2的生物学意义。
Both orthosteric and allosteric antagonists of the group II metabotropic glutamate receptors (mGlus) have been used to establish a link between mGlu(2/3) inhibition and a variety of CNS diseases and disorders. Though these tools typically have good selectivity for mGlu(2/3) versus the remaining six members of the mGlu family, compounds that are selective for only one of the individual group II mGlus have proved elusive. Herein we report on the discovery of a potent and highly selective mGlu2 negative allosteric modulator 58 (VU6001192) from a series of 4-oxo-1-aryl-1,4-dihydroquinoline-3-carboxamides. The concept for the design of this series centered on morphing a quinoline series recently disclosed in the patent literature into a chemotype previously used for the preparation of muscarinic acetylcholine receptor subtype 1 positive allosteric modulators. Compound 58 exhibits a favorable profile and will be a useful tool for understanding the biological implications of selective inhibition of mGlu2 in the CNS.