作为双重亲代谢型谷氨酸受体2/3负变构调节剂的取代吡唑并[1,5-a]喹唑啉的合成与构效关系
Synthesis and SAR of substituted pyrazolo[1,5-a]quinazolines as dual mGlu(2)/mGlu(3) NAMs.
作者信息
Wenthur Cody J, Morrison Ryan D, Daniels J Scott, Conn P Jeffrey, Lindsley Craig W
机构信息
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; 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. 2014 Jun 15;24(12):2693-8. doi: 10.1016/j.bmcl.2014.04.051. Epub 2014 Apr 20.
Herein we report the design and synthesis of a series of substituted pyrazolo[1,5-a]quinazolin-5(4H)-ones as negative allosteric modulators of metabotropic glutamate receptors 2 and 3 (mGlu2 and mGlu3, respectively). Development of this series was initiated by reports that pyrazolo[1,5-a]quinazoline-derived scaffolds can yield compounds with activity at group II mGlu receptors which are prone to molecular switching following small structural changes. Several potent analogues, including 4-methyl-2-phenyl-8-(pyrimidin-5-yl)pyrazolo[1,5-a]quinazolin-5(4H)-one (10b), were discovered with potent in vitro activity as dual mGlu2/mGlu3 NAMs, with excellent selectivity versus the other mGluRs.
在此，我们报道了一系列取代的吡唑并[1,5-a]喹唑啉-5(4H)-酮的设计与合成，这些化合物作为代谢型谷氨酸受体2和3（分别为mGlu2和mGlu3）的负变构调节剂。该系列化合物的研发源于有报道称，吡唑并[1,5-a]喹唑啉衍生的骨架能够产生对II组代谢型谷氨酸受体有活性的化合物，这些化合物在结构发生微小变化后容易发生分子转换。我们发现了几种强效类似物，包括4-甲基-2-苯基-8-(嘧啶-5-基)吡唑并[1,5-a]喹唑啉-5(4H)-酮（10b），它们作为双mGlu2/mGlu3负变构调节剂具有强效的体外活性，对其他代谢型谷氨酸受体具有出色的选择性。
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