VU6010608, a Novel mGlu7 NAM from a Series of N-(2-(1 H-1,2,4-Triazol-1-yl)-5-(trifluoromethoxy)phenyl)benzamides

Carson W Reed; Kevin M McGowan; Paul K Spearing; Branden J Stansley; Hanna F Roenfanz; Darren W Engers; Alice L Rodriguez; Eileen M Engelberg; Vincent B Luscombe; Matthew T Loch; Daniel H Remke; Jerri M Rook; Anna L Blobaum; P Jeffrey Conn; Colleen M Niswender; Craig W Lindsley

doi:10.1021/acsmedchemlett.7b00429

VU6010608, a Novel mGlu₇ NAM from a Series of N-(2-(1 H-1,2,4-Triazol-1-yl)-5-(trifluoromethoxy)phenyl)benzamides

ACS Med Chem Lett. 2017 Nov 8;8(12):1326-1330. doi: 10.1021/acsmedchemlett.7b00429. eCollection 2017 Dec 14.

Authors

Carson W Reed¹, Kevin M McGowan¹, Paul K Spearing¹, Branden J Stansley¹, Hanna F Roenfanz¹, Darren W Engers¹, Alice L Rodriguez¹, Eileen M Engelberg¹, Vincent B Luscombe¹, Matthew T Loch¹, Daniel H Remke¹, Jerri M Rook¹, Anna L Blobaum¹, P Jeffrey Conn^{1

2}, Colleen M Niswender^{1

2}, Craig W Lindsley^{1

1}

Affiliations

¹ Vanderbilt Center for Neuroscience Drug Discovery, Department of Pharmacology, and Department of Biochemistry and Chemistry, Vanderbilt University, Nashville, Tennessee 37232, United States.
² Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States.

Abstract

Herein, we report the structure-activity relationships within a series of mGlu₇ NAMs based on an N-(2-(1H-1,2,4-triazol-1-yl)-5-(trifluoromethoxy)phenyl)benzamide core with excellent CNS penetration (K_p 1.9-5.8 and K_p,uu 0.4-1.4). Analogues in this series displayed steep SAR. Of these, VU6010608 (11a) emerged with robust efficacy in blocking high frequency stimulated long-term potentiation in electrophysiology studies.