Persistent challenges in the development of an mGlu7 PAM in vivo tool compound: The discovery of VU6046980. (15th January 2023)

• Record Type: Journal Article
• Authors: Kalbfleisch, Jacob J.; Rodriguez, Alice L.; Lei, Xia; Weiss, Kelly; Blobaum, Annie L.; Boutaud, Olivier; Niswender, Colleen M.; Lindsley, Craig W.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 80(2023)
• Publication Date: 2023-01-15
• Subjects: Metabotropic glutamate receptor (mGlu) -- mGlu7 -- Positive allosteric modulator (PAM) -- GPCR; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2022.129106
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: 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.