Central Nervous System Disorders - Schizophrenia

Program Objective:

Schizophrenia is a debilitating psychiatric disorder affecting approximately 1% of the population.  This disorder is associated with periods of psychotic hallucinations and paranoid or bizarre delusions which are collectively characterized as the positive symptoms of schizophrenia. 

In addition, patients can also exhibit symptoms of social withdrawal (negative) and significant cognitive impairment. Traditionally, anti-psychotic medications have targeted the dopamine-2 receptor (D2), which has been effective in treating the positive symptoms, but less successful against the negative and cognitive symptoms of schizophrenia.  In addition, all currently available anti-psychotic medications cause significant side-effects that are believed to be the result of interactions with various off-target receptors in the central nervous system. 

Despite the number of anti-psychotic medications currently available, the treatment of schizophrenia remains an unmet medical need. Emerging evidence in the field has identified a new target for the treatment of schizophrenia, the glycine transporter 1 (GlyT-1), which provides an opportunity to treat all of the symptoms of schizophrenia in the absence of off-target side-effects.

Current Status:

The GlyT-1 program is currently in the Lead Optimization phase.  Through high throughput screening and synthetic chemistry efforts, AMRI has identified a novel series of GlyT-1 inhibitors, an emerging target for the treatment of schizophrenia.  In preclinical studies, these compounds have shown excellent potency in an animal efficacy model and selectivity without the side-effect profile of traditional anti-psychotic medications.  AMRI continues to develop the lead series and backup series of GlyT-1 inhibitors to optimize the drug-like characteristics for advancement into preclinical development.

Glutamate Hypothesis and Treating NMDA Receptor Hypofunction

A new hypothesis has developed from the observations that blockade of the NMDA (N-methyl D-aspartate) glutamate receptor can precipitate schizophrenic-like symptoms in both normal humans and animal models of the disease.  This hypothesis stipulates that reduced activation of the glutamatergic signaling pathways through the NMDA receptor is the underlying cause of the symptoms of schizophrenia. Glutamate, the main excitatory neurotransmitter in the CNS, is the primary ligand for the NMDA receptor, but this receptor also requires binding of glycine for activation.

Selective inhibition of GlyT-1 is expected to increase glycine levels in close proximity to the NMDA receptor. Increasing glycine levels in the synapse is anticipated to counteract the reduced function of the NMDA receptor; therefore, the activation of the downstream neurons in response to glutamate release will be normalized.

AMRI believes that inhibitors of GlyT-1 will provide a differentiated treatment for not only the positive, but also the negative and cognitive symptoms of schizophrenia without inducing the side-effects associated with the anti-psychotic medications on the market today.  The recent positive phase II results of Roche’s compound (R1678) in improving the negative symptoms of schizophrenia and patient’s personal and social performance has stimulated further interest in the development of GlyT-1 inhibitors.