While treatments exist for positive symptoms of schizophrenia in the form of atypical antipsychotics, no approved therapies exist for the concomitant negative symptoms or cognitive impairment associated with schizophrenia (CIAS).  The key second messenger molecules cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) have been implicated as playing a major role in cognitive processes.  Phosphodiesterase 2A (PDE2A), which hydrolyzes both cGMP and cAMP, has highest levels of expression within limbic and basal ganglia brain circuitry found to be dysfunctional in schizophrenia.  Inhibitors of PDE2A would increase cyclic nucleotide levels in these key brain regions and could thus potentially improve cognitive processes.  This presentation will detail the identification of a hit series via high-throughput screening (HTS), and the strategic application of parallel synthesis, fragment and structure-based design to improve potency, selectivity, ADME and safety to yield a clinical candidate.  The pre-clinical biological profile and first-in-human pharmacokinetic data will be presented.

Identification of a brain penetrant, highly selective phosphodiesterase 2A inhibitor for the treatment of cognitive impairment associated with schizophrenia (CIAS)

244th National Meeting (2012)

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