AMG 747, a novel glycine transporter type-1 (GLyT1) inhibitor with cognition-enhancing and antipsychotic-like effects in preclinical rodent models of schizophrenia

Abstract

Background: Evidence suggests that NMDA receptor hypofunction is involved in the pathogenesis of schizophrenia. The NMDA receptor is activated by two co-agonists, glutamate and glycine. Elevating brain glycine levels, by inhibiting GlyT1, is a potentially novel way to enhance NMDA receptor function. AMG 747 is a highly selective, orally bioavailable, and brain-penetrant small molecule inhibitor of GlyT1. Methods: In a series of in vitro and in vivo characterization studies, we evaluated the in vitro potency and selectivity of AMG 747, the pharmacodynamic elevation of brain glycine levels, and the efficacy of AMG 747 in rodent models of cognitive and positive symptoms. Results: In vitro cell-based assays demonstrate that AMG 747 is a potent inhibitor of GlyT1 with IC50 values of approximately 75, 95, and 205 nM against human, rat, and dog GlyT1, respectively, and >100-fold selective over the second member of the glycine transporter family, human GlyT2. AMG 747 has selectivity across a broad panel of >150 GPCRs, ion channels, kinases, and transporters, including both strychnine-sensitive and -insensitive glycine binding sites and glutamate binding sites on the NMDA receptor. AMG 747 displays promising pharmacokinetic (PK) properties (rat t1/2: 2.9h) and nearly complete bioavailability in rats, with projected human PK suitable for chronic daily oral administration. In preclinical rodent species, AMG 747 demonstrates pharmacodynamic effects on rat CSF glycine content, in both a dose and time dependent fashion (minimal effective dose (MED) 0.3mg/kg PO; CSF glycine [Emax]∼300% increase over baseline at 30mg/ kg). Additionally, systemic administration of AMG 747 in rats leads to elevations in interstitial glycine in the prefrontal cortex measured by in vivo microdialysis. In a subchronic PCP-induced model producing a cognitive deficit in rats, AMG 747 produces a statistically significant improvement in the novel object recognition (NOR) task (MED 0.1mg/kg PO). Furthermore, NOR performance is enhanced by AMG 747 in naïve rats (MED 0.3mg/kg PO). Finally, AMG 747 has been shown to reduce the hyperactivity caused by NMDA receptor antagonism in mice similar to that observed with known antipsychotic drugs. Conclusion: In light of other published data on GlyT1 inhibitors, our results warrant further investigation of AMG 747 as a potential treatment for cognitive, negative, and positive symptoms in schizophrenia.