Persistent challenges in the development of an mGlu7 PAM in vivo tool compound: The discovery of VU6046980

• Published in: Bioorganic & medicinal chemistry letters 2023-01, Vol.80, p.129106-129106, Article 129106
• Main Authors: Kalbfleisch, Jacob J., Rodriguez, Alice L., Lei, Xia, Weiss, Kelly, Blobaum, Annie L., Boutaud, Olivier, Niswender, Colleen M., Lindsley, Craig W.
• Format: Article
• Language: English
• Subjects: GPCR; Metabotropic glutamate receptor (mGlu); mGlu7; Positive allosteric modulator (PAM)
• ISSN: 0960-894X; 1464-3405; 1464-3405
• DOI: 10.1016/j.bmcl.2022.129106

[Display omitted] Herein, we report on the further chemical optimization of the first reported mGlu7 positive allosteric modulator (PAM), VU6027459. Replacement of the quinoline core by a cinnoline scaffold increased mGlu7 PAM potency by ∼ 10-fold, and concomitant introduction of a chiral tricyclic motif led to potent mGlu7 PAMs with enantioselective mGlu receptor selectivity profiles. Of these, VU6046980 emerged as a putative in vivo tool compound with excellent CNS penetration (Kp = 4.1; Kp,uu = 0.7) and efficacy in preclinical models. However, either off-target activity at the sigma-1 receptor or activity at a target not elucidated by large ancillary pharmacology panels led to sedation not driven by activation of mGlu7 (validated in Grm7 knockout mice). Thus, despite a significant advance, a viable mGlu7 PAM in vivo tool remains elusive.