Reed Carson W, Kalbfleisch Jacob J, Wong Madison J, Washecheck Jordan P, Hunter Ashton, Rodriguez Alice L, Blobaum Anna L, Conn P Jeffrey, Niswender Colleen M, Lindsley Craig W
Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37232, United States.
Warren Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
ACS Med Chem Lett. 2020 Aug 20;11(9):1773-1779. doi: 10.1021/acsmedchemlett.0c00432. eCollection 2020 Sep 10.
Herein, we report the discovery of the first selective and CNS penetrant mGlu PAM (VU6027459) derived from a "molecular switch" within a selective mGlu NAM chemotype. VU6027459 displayed CNS penetration in both mice (K = 2.74) and rats (K= 4.78), it was orally bioavailable in rats (%F = 69.5), and undesired activity at DAT was ablated.
在此,我们报告了首个源自选择性代谢型谷氨酸负变构调节剂(NAM)化学类型中的“分子开关”的选择性且可穿透中枢神经系统的代谢型谷氨酸正变构调节剂(mGlu PAM,VU6027459)的发现。VU6027459在小鼠(K = 2.74)和大鼠(K = 4.78)中均表现出中枢神经系统穿透性,在大鼠中具有口服生物利用度(%F = 69.5),并且消除了在多巴胺转运体(DAT)上的不良活性。