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

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  1 , Kevin M McGowan  1 , Paul K Spearing  1 , Branden J Stansley  1 , Hanna F Roenfanz  1 , Darren W Engers  1 , Alice L Rodriguez  1 , Eileen M Engelberg  1 , Vincent B Luscombe  1 , Matthew T Loch  1 , Daniel H Remke  1 , Jerri M Rook  1 , Anna L Blobaum  1 , P Jeffrey Conn  1   2 , Colleen M Niswender  1   2 , Craig W Lindsley  1   1
Affiliations

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 et al. ACS Med Chem Lett. .

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 (Kp 1.9-5.8 and Kp,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.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Structures of the recently reported mGlu7-preferring PAM (1) and mGlu7 NAMs (2–4), with a conserved 5,6-bicyclic chemotype.
Figure 2
Figure 2
Structure of HTS hit 5 (VU6009748), and the multiple regions to be surveyed in the lead optimization campaign.
Scheme 1
Scheme 1. Synthesis of Analogues 11
Reagents and conditions: (a) R1X, K2CO3, DMF, 100 °C, 3h, 94–97%; (b) LiOH, THF:H2O (1:1), 60 °C, 2 h, quantitative; (c) PyClU, DIEA, CH2Cl2, 100 °C, mw, 20 min, 47–82%; azaheterocycle, N,N-dimethylcyclohexane-1,2-diamine, K3PO4, CuI, DMF, 100 °C, 16h, 51–68%.
Figure 3
Figure 3
Substituents explored in analogs 11 that were inactive as mGlu7 NAMs (IC50s > 10 μM).
Figure 4
Figure 4
HFS-induced LTP is blocked by the mGlu7 NAM VU6010608 (11a). (A) Time course showing the effects of vehicle or mGlu7 NAM (VU6010608, 10 μM, gray symbols) followed by high-frequency stimulation (HFS; 2 × 100 Hz, 20 s ISI) on fEPSP slope. (B) Comparison between drug treatment groups based on average slope from last 5 min of recording. (**p < 0.01 compared to vehicle; Student’s t test, n = 4 per group). Data are expressed as mean ± SEM.
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