Discovery of VU6024578/BI02982816: An mGlu Positive Allosteric Modulator with Efficacy in Preclinical Antipsychotic and Cognition Models.

Herein, we report progress toward a metabotropic glutamate receptor subtype 1 (mGlu) positive allosteric modulator (PAM) clinical candidate and the discovery of VU6024578/BI02982816. From a weak high-throughput screening hit (VU0538160, EC > 10 μM, 71% Glu), optimization efforts improved functional potency over 185-fold to deliver the selective (inactive on mGlu) and CNS penetrant (rat K = 0.99, K = 0.

Positive allosteric modulators (PAMs) of the group II metabotropic glutamate receptors: Design, synthesis, and evaluation as ex-vivo tool compounds.

This letter describes synthesis and evaluation of two series of dual mGlu/mGlu positive allosteric modulators with moderate mGlu potency and robust mGlu potency in thallium flux assays. These compounds were profiled their ability to modulate mGlu-mediated signaling in central neurons by co-application of a selective mGlu NAM to isolate mGlu-selective effects. Using acute mouse brain slices from the prefrontal cortex, potentiation of group II mGlu receptor agonist Ca signaling in PFC pyramidal cells with either the dual mGlu/mGlu PAM 16e or 23d demonstrated effects mediated selectively via mGlu.