Discovery of VU6024578/BI02982816: An mGlu₁ Positive Allosteric Modulator with Efficacy in Preclinical Antipsychotic...

Herein, we report progress toward a metabotropic glutamate receptor subtype 1 (mGlu₁) positive allosteric modulator (PAM) clinical candidate and the discovery of VU6024578/BI02982816. From a weak high-throughput screening hit (VU0538160, EC₅₀ > 10 μM, 71% Glu_max), optimization efforts improved functional potency over 185-fold to deliver the selective (inactive on mGlu_2-5,7,8) and CNS penetrant (rat K_p = 0.99, K_p,uu = 0.82; MDCK-MDR1 ER = 1.7, P_app = 73 × 10-6 cm/s) mGlu₁ PAM (VU6024578/BI02982816, EC₅₀ = 54 nM, 83% Glu_max). An excellent rat pharmacokinetic profile allowed the evaluation of VU6024578/BI02982816 in both amphetamine-induced hyperlocomotion (minimum effective dose (MED) = 3 mg/kg, p.o.) and MK-801 induced disruptions of novel object recognition (MED = 10 mg/kg p.o.), thus providing efficacy in preclinical models of psychosis and cognition. However, unanticipated AEs in dog prevented further consideration as a candidate. Thus, VU6024578/BI02982816 can serve as a best-in-class in vivo rodent tool to study selective mGlu₁ activation.