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

Jacob J Kalbfleisch; Alice L Rodriguez; Xia Lei; Kelly Weiss; Annie L Blobaum; Olivier Boutaud; Colleen M Niswender; Craig W Lindsley

doi:10.1016/j.bmcl.2022.129106

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

Bioorg Med Chem Lett. 2023 Jan 15:80:129106. doi: 10.1016/j.bmcl.2022.129106. Epub 2022 Dec 15.

Authors

Jacob J Kalbfleisch¹, Alice L Rodriguez², Xia Lei², Kelly Weiss², Annie L Blobaum², Olivier Boutaud², Colleen M Niswender³, Craig W Lindsley⁴

Affiliations

¹ Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA.
² Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
³ Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. Electronic address: colleen.m.niswender@vanderbilt.edu.
⁴ Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. Electronic address: craig.lindsley@vanderbilt.edu.

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.

Keywords: GPCR; Metabotropic glutamate receptor (mGlu); Positive allosteric modulator (PAM); mGlu(7).

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

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