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ID: ALA5236641

Journal: Bioorg Med Chem Lett

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

Authors: Kalbfleisch JJ, Rodriguez AL, Lei X, Weiss K, Blobaum AL, Boutaud O, Niswender CM, Lindsley CW.

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 (K_p = 4.1; K_p,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.

CiteXplore: 36528230

DOI: 10.1016/j.bmcl.2022.129106