?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 40% 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-2 (PDE2), 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 PDE2 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 PDE2 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 (PDE1), 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. O'Donnell and Ying Xu at the SUNY at Buffalo, experts in the characterization of antianxiety and antidepressant effects of PDE2 inhibition, to test the behavioral efficacy of these molecules. We plan to optimize lead PDE2 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., BAY60-7550). Up to five compounds will be tested in a panel of antianxiety and antidepressant paradigms in the Ying/O'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 PDE2 inhibitors in animal models relevant t other features of neurodevelopmental diseases such as ASD, including social behavior and hyperactivity.
Public Health Relevance Statement: Public Health Relevance: Intra-Cellular Therapies, Inc. ("ITI"), 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 ITI's proprietary compound library we will identify and develop promising drug leads as CNS drug candidates.
NIH Spending Category: Anxiety Disorders; Autism; Behavioral and Social Science; Brain Disorders; Depression; Intellectual and Developmental Disabilities (IDD); Mental Health; Mental Illness; Neurosciences; Pediatric; Schizophrenia; Serious Mental Illness
Project Terms: Address; Adverse effects; Affect; Aggressive behavior; Agitation; Animal Model; Animal Testing; Animals; Anti-Anxiety Agents; antidepressant effect; Antidepressive Agents; Anxiety; Anxiety Disorders; anxiety symptoms; anxiety treatment; anxiety-like behavior; autism spectrum disorder; Autistic Disorder; base; behavior test; Behavioral; Behavioral Paradigm; Binding; Bioavailable; Biological Assay; Biological Availability; biophysical properties; Biotechnology; Brain; Brain region; Buffaloes; Cell Culture Techniques; Cells; Central Nervous System Diseases; Clinical; clinical investigation; Cognition; Cognition Disorders; Cognitive; Corpus striatum structure; CREB1 gene; Cyclic AMP; Cyclic GMP; Cyclic Nucleotides; Data; depressive symptoms; Development; Disease; drug candidate; drug discovery; Drug Targeting; Enzymes; Exhibits; experience; Family; Family member; feeding; Future; Genes; Half-Life; Hippocampus (Brain); Hyperactive behavior; improved; In Vitro; inhibitor/antagonist; innovation; Lead; Libraries; Literature; Mental Depression; Metabolic; Metabolism; Modeling; Molecular Target; Monitor; Mood Disorders; Moods; Motor Activity; Mus; Neurodevelopmental Disorder; new therapeutic target; New York; novel; novel therapeutics; Oral; Patients; Penetrance; Penetration; Permeability; Personal Communication; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phosphodiesterase Inhibitors; phosphoric diester hydrolase; Plasma; pre-clinical; Preparation; Principal Investigator; Program Development; programs; Proteins; public health relevance; Publishing; Reporting; research clinical testing; restraint stress; RNA Splicing; Rodent; Safety; scaffold; Schizophrenia; Scientist; screening; Sedation procedure; Selective Serotonin Reuptake Inhibitor; Signal Transduction; Small Business Innovation Research Grant; small molecule; small molecule inhibitor; small molecule therapeutics; Social Behavior; Social Interaction; Social isolation; Staging; Stress; symptom treatment; Tail Suspension; Testing; Therapeutic; Therapeutic Agents; tool; Universities; Variant; vasodilator-stimulated phosphoprotein; Vulnerable Populations; Work
