Development of PDE2 Inhibitors for Treatment of Anxiety/Depression in Autism/Schizophrenia

DESCRIPTION provided by applicant Anxiety and depression are prevalent in patients affected by neurodevelopmental disorders including autism spectrum disorders ASD and schizophrenia These co morbid disorders contribute to abnormal social interaction and deficits in interpersonal communication that intensify the social isolation in patients It is noteworthy tht over of ASD patients experience at least one anxiety disorder while co morbid depression is present in the majority of schizophrenia patients Significantly current anti depressant medications are reported to be minimally effective in these patients and often seriously exacerbate hyperactivity aggression and irritability New therapeutic agents that effectively improve mood in patients with these neurodevelopmental disorders without promoting hyperactivity or aggression would be highly significant and are urgently needed Here we propose a one year Phase I SBIR project to advance inhibitors of phosphodiesterase PDE a novel preclinical target for treatment of anxiety and depression into preclinical animal testing as first in class treatments for mood disorders in neurodevelopmental disease The PDE enzyme controls levels of cyclic nucleotides cAMP and cGMP in brain regions involved in cognition and mood including cortex hippocampus and striatum Published tool compounds inhibiting PDE activity display antianxiety like and antidepressant like efficacy in animal behavioral paradigms though these compounds have generally poor bioavailability and exhibit limited brain permeability hindering their clinical development to date Intra Cellular Therapies Inc ITI a clinical stage pharmaceutical company with an established drug discovery platform and expertise in discovering small molecule inhibitors for protein phosphodiesterases PDE has discovered small molecule inhibitors of the enzyme with nM potency good selectivity versus other PDE families and superior bioavailability and brain penetrance versus published compounds ITI proposes to collaborate with Drs James M Oandapos Donnell and Ying Xu at the SUNY at Buffalo experts in the characterization of antianxiety and antidepressant effects of PDE inhibition to test the behavioral efficacy of these molecules We plan to optimize lead PDE inhibitors with comparable or better potency low nM and selectivity versus other PDE family enzymes and improved oral bioavailability and metabolic stability compared with to published compounds e g BAY Up to five compounds will be tested in a panel of antianxiety and antidepressant paradigms in the Ying Oandapos Donnell lab to select molecules with superior efficacy for advancement into a preclinical development program in a future Phase II SBIR application We propose to extend these studies if successful during a Phase II project to investigate the utility and potential side effects of PDE inhibitors in animal models relevant t other features of neurodevelopmental diseases such as ASD including social behavior and hyperactivity PUBLIC HEALTH RELEVANCE Intra Cellular Therapies Inc andquot ITIandquot has a biotechnology platform that has enabled discovery of innovative pharmaceutical therapies for CNS disorders based on intracellular signaling In this project we propose to develop safe brain penetrant drugs targeting a molecular target in the brain that affects intracellular signaling and advance these drugs as treatment for symptoms of depression and anxiety in schizophrenia By screening of the ITIandapos s proprietary compound library we will identify and develop promising drug leads as CNS drug candidates