VU0361737

Although VU0361737 has a decent cellular EC50 of 240 nM in a distal functional assay, the probe lacks any proof for a proximal interaction with the proposed target mGluR4. In addition, https://doi.org/10.1016/j.neuint.2020.104770 already describes some mGluR independent anti-inflammatory actions of VU0361737. The availability of significantly less active, but structurally related control molecules is a plus, but neither VU0361737 nor its inactive control compounds have been characterized in toxicological relevant or non-target expressing cells/cell lines to assess potential off-target activities. No pharmacological in vivo activity has been described for VU0361737. The compound is only assessed in pharmacokinetic experiments. The low metabolic stability in combination with a low free fraction unbound in plasma is resulting in a very low unbound exposure in rats. To reach cellular relevant concentrations in vivo, a much higher dose would be needed, which is neither tested nor proven to be tolerated. In addition, the total brain exposure is not sufficient to extrapolate the required dose for a pharmacological activity in the CNS in the absence of an understanding of the Kpuu.

Based on the data shared in (J. Med. Chem. 2009, 52, 4115–4118 4115 DOI: 10.1021/jm9005065), VU0361737 appears on the surface to be a useful cellular probe for mGluR4, particularyl considering its potency and selectivity vs other mGluR familiy members. The later reference (Neurochemistry International 2020, 138, 104770 DOI 10.1016/j.neuint.2020.104770) casts some doubt as it appears there may be off-target effects at relevant concentrations, so further characterisation would be needed before it could be recommended. Although PK data show some brain exposure after dosing at 10 mg/kg ip, much more characterisation (e.g. timecourse, free concentrations, tolerability) is required before this compound can be recommended as an in vivo probe.