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Novel 2-methoxyacylhydrazones as potent, selective PDE10A inhibitors with activity in animal models of schizophrenia

Schizophrenia is a debilitating disease affecting approximately 1% of the world population. 1 Current pharmaceutical agents used to treat schizophrenia include the typical antipsychotics that effectively address positive symptoms such as hallucinations and delusions. These drugs exert their effect through action as D2 receptor antagonists. However, some drawbacks of these medications are motor side effects and lack of efficacy in a subset of the patient population. 2 Contemporary ‘atypical’ antipsychotics possessing mixed D2/5HT2A antagonism have reduced severity of motor side effects, but can cause deleterious metabolic consequences. Besides the need for new antipsychotic agents without unwanted side effects, pharmaceuticals are needed that address cognitive symptoms which include impairment of working memory and executive function as well as negative symptoms such as social withdrawal. The severity of the cognitive effects of schizophrenia has been shown to be a predominant determinant in the overall prognosis of patient function. Thus, pharmaceutical entities for schizophrenia are needed that can manage both positive and negative symptoms along with cognitive deficits. Phosphodiesterase 10A (PDE10A) is a dual-specificity phosphodiesterase that hydrolyzes both cyclic adenosine and cyclic guanosine monophosphate (cAMP and cGMP). 3a It is expressed predominantly in brain, with highest concentrations in the medium spiny http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Bioorganic & Medicinal Chemistry Letters Elsevier
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