Novel PDE Inhibitors for Treatment of Cognitive Dysfunction in Schizophrenia

DESCRIPTION (provided by applicant): This proposal is submitted as a Phase II SBIR application, pursuant to our existing Phase I grant, which was funded in response to the NIMH Program Announcement #PA-02-027 entitled: "Pharmacological agents and drugs for mental disorders". The development of new pharmaceuticals for neuropsychiatric disorders is limited by the lack of rapid and effective methods to evaluate potentially useful compounds that arise from primary high throughput screens. As a result of our Phase I grant, ITI has developed a technological platform based on measurements of levels of physiologically-relevant phosphoproteins involved in mediating the effects of neurotransmitters. This platform, based on measurements of changes in protein phosphorylation after treatment of mice in vivo with standard compounds, has been used to profile effects of all known antidepressant drug classes to produce a reference database. Results comprising this database, reviewed in this application, indicate that clinically-efficacious antidepressants characteristically increase the state of phosphorylation in vivo of the dopamine and cAMP-regulated phosphoprotein of Mr=32kDa (DARPP-32) and certain of its downstream targets, including the AMPA receptor subunit, GluR1. The comprehensive goal of this Phase II application is to establish and pursue a drug development program aimed at obtaining a small-molecule inhibitor of PDE1B, the Ca2+/calmodulin-dependent phosphodiesterase 1B, suitable for use as an antidepressant medication, including depression in patients with AIDS or other CNS disorders. To that end we propose the following aims: (I) To develop a screening assay for identifying inhibitors of PDE1B, (II) To screen libraries for the purpose of generating lead compounds, (III) To utilize phospho-profiling methods developed during our Phase I award to assist in optimization of lead compounds, and (IV) To evaluate the efficacy of PDE1B inhibitors as antidepressant medications using a panel of behavioral tests for antidepressant action. Recent results are promising and include: identification of a number of low nanomolar PDE-1B inhibitor "lead" structures, establishment of a high capacity screening assay, and cloning of a full-length human PDE-1B enzyme. In addition to substantial resources already committed, we plan to dedicate further resources in chemistry, and behavioral testing. We have developed a detailed plan to assess potential toxicities associated with PDE-1B inhibitors.