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This review is based on peer-reviewed published articles, and summarizes the cellular and molecular biology of PDE10 as a rational target for psychiatric and neurodegenerative drug discovery. Here, we present the classification of PDE10-Is from a medicinal chemistry point of view across a wide range of different, drug-like chemotypes starting from theophylline and caffeine analogs, papaverine and dimethoxy catechol type PDE10-Is, TP-10, MP-10, MP-10/papaverine/quinazoline series inhibitors, and ending with the newest inhibitors obtained from fragment-based lead discovery (FBLD). The authors have collated recent research on inhibition of PDE10A as a promising therapeutic strategy for psychiatric and neurodegenerative diseases, based on its efficacy in animal models of schizophrenia, Parkinson's, Huntington's, and Alzheimer's diseases. This review also presents pharmacological data on PDE10-Is as possible therapeutics for the treatment of cognitive deficits, obesity and depression. Moreover, it summarizes the current strategies for PDE10-Is drug discovery based on the results of clinical trials. The authors also present the latest studies on crystal structures of PDE10 complexes with novel inhibitors.

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