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

Authors

Reed CW Carson W , Kalbfleisch JF Jacob F , Turkett JA Jeremy A , Trombley TA Trevor A , Nastase AF Anthony F , Spearing PK Paul K , Haymer DH Daniel H , Sarwar MM Mohammad Moshin , Quitalig M Marc , Dickerson JW Jonathan W , Blobaum AL Annie L , Boutaud O Olivier , Voehringer P Patrizia , Schuelert N Niklas , Cho HP Hyekyung P , Niswender CM Colleen M , Rook JM Jerri M , Priepke H Henning , Ursu D Daniel , Conn PJ P Jeffrey , Melancon BJ Bruce J , Lindsley CW Craig W .
Journal of medicinal chemistry. 2024 12 12; 67(24).
22291-22312

PMID: 39665415

Abstract

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 = 0.82; MDCK-MDR1 ER = 1.7, P = 73 × 10-6 cm/s) mGlu PAM (VU6024578/BI02982816, EC = 54 nM, 83% Glu). 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 rodent tool to study selective mGlu activation.