Malosh Chrysa, Turlington Mark, Bridges Thomas M, Rook Jerri M, Noetzel Meredith J, Vinson Paige N, Steckler Thomas, Lavreysen Hilde, Mackie Claire, Bartolomé-Nebreda José M, Conde-Ceide Susana, Martínez-Viturro Carlos M, Piedrafita María, Sánchez-Casado M Rosa, Macdonald Gregor J, Daniels J Scott, Jones Carrie K, Niswender Colleen M, Conn P Jeffrey, Lindsley Craig W, Stauffer Shaun R
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; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, 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; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA.
Bioorg Med Chem Lett. 2015 Nov 15;25(22):5115-20. doi: 10.1016/j.bmcl.2015.10.009. Epub 2015 Oct 9.
We report the optimization of a series of metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs) from an acyl dihydropyrazolo[1,5-a]pyrimidinone class. Investigation of exocyclic amide transpositions with this unique 5,6-bicyclic core were conducted in attempt to modulate physicochemical properties and identify a suitable backup candidate with a reduced half-life. A potent and selective PAM, 1-(2-(phenoxymethyl)-6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)ethanone (9a, VU0462807), was identified with superior solubility and efficacy in the acute amphetamine-induced hyperlocomotion (AHL) rat model with a minimum effective dose of 3mg/kg. Attempts to mitigate oxidative metabolism of the western phenoxy of 9a through extensive modification and profiling are described.
我们报道了一系列来自酰基二氢吡唑并[1,5-a]嘧啶酮类的代谢型谷氨酸受体5（mGlu5）正变构调节剂（PAM）的优化情况。针对具有这种独特5,6-双环核心的环外酰胺转位进行了研究，试图调节理化性质并确定一种半衰期较短的合适备用候选物。在急性苯丙胺诱导的大鼠活动亢进（AHL）模型中，鉴定出一种强效且选择性的PAM，即1-(2-(苯氧基甲基)-6,7-二氢吡唑并[1,5-a]嘧啶-4(5H)-基)乙酮（9a，VU0462807），其溶解度和效力更佳，最小有效剂量为3mg/kg。还描述了通过广泛修饰和分析来减轻9a的苯氧基西侧氧化代谢的尝试。
