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

ABSTRACT: 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

SUBMITTER: Reed CW 

PROVIDER: S-EPMC11684029 | biostudies-literature | 2024 Dec

REPOSITORIES: biostudies-literature