Discovery of VU6024578/BI02982816:\nAn mGlu<sub>1</sub> Positive Allosteric Modulator with Efficacy in\nPreclinical Antipsychotic\nand Cognition Models

Herein, we report\nprogress toward a metabotropic glutamate receptor\nsubtype 1 (mGlu<sub>1</sub>) positive allosteric modulator (PAM) clinical\ncandidate and the discovery of VU6024578/BI02982816. From a weak high-throughput\nscreening hit (VU0538160, EC<sub>50</sub> > 10 μM, 71% Glu<sub>max</sub>), optimization efforts improved functional potency over\n185-fold to deliver the selective (inactive on mGlu<sub>2–5,7,8</sub>) and CNS penetrant (rat K<sub>p</sub> = 0.99, K<sub>p,uu</sub> =\n0.82; MDCK-MDR1 ER = 1.7, P<sub>app</sub> = 73 × 10–6\ncm/s) mGlu<sub>1</sub> PAM (VU6024578/BI02982816, EC<sub>50</sub> =\n54 nM, 83% Glu<sub>max</sub>). An excellent rat pharmacokinetic profile\nallowed the evaluation of VU6024578/BI02982816 in both amphetamine-induced\nhyperlocomotion (minimum effective dose (MED) = 3 mg/kg, p.o.) and\nMK-801 induced disruptions of novel object recognition (MED = 10 mg/kg\np.o.), thus providing efficacy in preclinical models of psychosis\nand cognition. However, unanticipated AEs in dog prevented further\nconsideration as a candidate. Thus, VU6024578/BI02982816 can serve\nas a best-in-class <i>in vivo</i> rodent tool to study selective\nmGlu<sub>1</sub> activation.