Novel PDE Inhibitors for Treatment of Cognitive Dysfunction in Schizophrenia

Schizophrenia is a chronic, severe, disabling brain disorder with positive symptoms such as hallucinations and delusions, negative symptoms such as a lack of affect or pleasure in life, and cognitive symptoms such as trouble with focusing and difficulty with working memory. Scientists believe that an imbalance in brain chemistry, especially involving dopamine, an important brain-signaling chemical, causes the symptoms. Schizophrenia affects about 1 percent of the population, but it occurs in about 10 percent of those who have a close relative with the disorder. A number of antipsychotic medications are currently prescribed for schizophrenia, but patients respond to these differently, and a person may need to try several before finding one that helps. These researchers are developing a new drug to reverse the cognitive symptoms of schizophrenia. It works by inhibiting an enzyme called phosphodiesterase 1B to restore function in the dopamine D1 receptor in a part of the brain called the prefrontal cortex.

Scientific Synopsis

Intra-Cellular Therapies, Inc. (ITI), is developing a clinical candidate based upon the target mechanism of inhibition of the brain-enriched phosphodiesterase 1B (PDE1B). This is a novel target that has not been used as a drug target but has been extensively documented by the research at ITI. Under support, in part, from the SBIR program at NIMH, we have developed an inhibitor of this enzyme and are currently scaling up synthesis for preclinical testing necessary to support an Investigational New Drug (IND) application. This inhibitor is indicated as an agent to reverse the cognitive dysfunction in schizophrenia and, in particular, the dopamine D1 receptor hypo-functionality in the prefrontal cortex, a mechanism known to be associated with this disease. Our efforts are designed to focus eventually on a human Phase II clinical proof-of-concept trial to fully validate this novel mechanism. As part of its support for this development program, ITI has begun the GLP scale-up synthesis of the development candidate that will be used for the preclinical work.

Lead Collaborator

Intra-Cellular Therapies, Inc., New York
, New York
Lawrence Wennogle, Ph.D.

Public Health Impact

This program addresses an enormous unmet medical need. Schizophrenia occurs in more than 1 percent of the adult population, and cognitive dysfunction is recognized as a profound contributor to the disorder. Due to the lifelong nature of the disease, schizophrenia has been defined as the single largest drain on the national medical budget.


Work on this project is complete. 

Project Details

  • Investigational New Drug (IND)-directed toxicology