Discovery of VU6066098: A Selective and CNS-Penetrant mGlu₂ NAM with Robust Antidepressant-, Antipsychotic-, and...

Herein, we report the discovery and development of an optimized mGlu₂ Negative Allosteric Modulator (NAM) in vivo tool compound, VU6066098, based on a novel, structurally distinct chemotype. VU6066098 is a potent, selective, and CNS-penetrant mGlu₂ NAM with excellent rat PK (CL_p = 23.9 mL/min/kg, t_1/2 = 2.2 h, %F = 100, K_p = 1.28, K_p,uu = 0.25), making it ideal to explore the therapeutic potential of selective mGlu₂ inhibition in preclinical rat models. In a rat forced swim test, VU6066098 displayed an oral minimum effective dose (MED) of 1 mg/kg and was equi-efficacious to ketamine. In amphetamine-induced hyperlocomotion, VU6066098 displayed an oral minimum effective dose (MED) of 30 mg/kg. While in the preclinical cognitive tasks of rat novel object recognition and acquisition of contextual fear conditioning, VU6066098 produced robust dose-dependent effects at oral minimum effective doses (MED) of 3 mg/kg and 0.3 mg/kg, respectively. In a blast-related traumatic brain injury (TBI) model, administration of VU6066098 at a dose of 10 mg/kg IP was effective acutely, and the effect on NOR memory was sustained up to 30 days postdose. Thus, mGlu₂ NAMs show therapeutic potential for the treatment of a broad range of affective and cognitive symptoms associated with Major Depressive Disorder, Alzheimer's disease, TBI, and acute psychosis; moreover, these data strongly support further optimization of mGlu₂ NAMs for future clinical development.