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Small molecule GlyT1 inhibitors as therapeutics for Schizophrenia or Parkinson's disease
Program and Background<?xml:namespace prefix = o ns = "urn:schemas-microsoft-com:office:office" />
Antipsychotic medications, which have been available since the mid-1950s, and work primarily by suppressing dopamine activity, are the current standard of treatment for schizophrenia. These are generally able to reduce hallucinations and delusions and allow patients to function more effectively and appropriately (reduced positive symptoms). These treatments are, however, less helpful with negative symptoms, which are harder to recognize and can be mistaken for depression, which include blunted emotions; lack of motivation; an inability to take an interest in, or enjoy, life; and poor social functioning.
Treatment of these negative symptoms has been a focus of one small molecule program within the Center for Neuroscience and Drug Discovery. Dysfunction of neurotransmission at the NMDA-type glutamate receptor has been implicated in the pathophysiology of schizophrenia, suggesting that enhancement of receptor function may be effective in treating schizophrenia; glycine transporter-1 (GlyT-1) inhibitors increase glycine levels and hence NMDA signaling. The lead compound has good PK/PD properties, several of which are highlighted in the table, and include not having significant off target effects.
Recently, Roche has reported a GlyT-1 inhibitor compound, RG1678, has entered Phase III trials and shown positive results on the negative symptoms of schizophrenia. These clinical trials further validate the target for the treatment of negative symptoms in schizophrenia. However recent data using GlyT-1 inhibitors in Parkinson’s models, have suggested that these may also be viable therapeutics for Parkinson’s disease as well.
Program Status and IP
Vanderbilt has initated IP protection for the different chemical series both within the US as well as internationally. The group is seeking a partner for further research and development of these compounds.
Inventors:P. Jeffrey ConnCraig LindsleyCharles David WeaverColleen NiswenderAlice RodriguezDouglas ShefflerRichard WilliamsCarrie Jones