Background: The phosphodiesterase 10 (PDE10) family, identified in 1999, is
mainly expressed in the brain, particularly in the striatum, within the medium spiny neurons,
nucleus accumbens, and olfactory tubercle. Inhibitors of PDE10 (PDE10-Is) are a conceptually
rational subject for medicinal chemistry with potential use in the treatment of psychiatric
and neurodegenerative diseases.
Objective: 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.