Phosphodiesterase 10 Inhibitors - Novel Perspectives for Psychiatric and Neurodegenerative Drug Discovery

Abstract

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.

The phosphodiesterase 10 inhibitor papaverine exerts anti-inflammatory and neuroprotective effects via the PKA signaling pathway in neuroinflammation and Parkinson’s disease mouse models

“…In addition, PDE10A has also been detected in parenchymal parts of the substantia nigra, globus pallidus, and striatonigral projections [24]. Therefore, several studies have suggested PDE10A as a potential therapeutic target for movement disorders such as PD and HD, and psychiatric disorders that affect the basal ganglia [25–27]. Currently, several PDE10A inhibitors are undergoing clinical trials in patients with HD and schizophrenia [28, 29].…”

Antidepressant-like activity and safety profile evaluation of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione derivatives as 5-HT1A receptor partial agonists

“…Phosphodiesterases (PDEs) have been shown to play distinct roles in the processes of emotion, while selective PDE inhibitors can modulate mood and emotional states by preventing the breakdown of cAMP and/or cGMP. Some members of the PDE family, such as PDE4B and PDE10A, may be good drug targets because of their presence in areas of the brain associated with the site of action of psychotropic drugs, and their inhibitors therefore have potential therapeutic relevance [50]. Certainly, we could exclude the inhibition of PDE4B and PDE10A as a potential mechanism of antidepressant-like action of AZ-853 and AZ-861; this is because in a previous in vitro study using a bioluminescent detection system, we demonstrated that both compounds did not induce PDE4B and PDE10A inhibitory activity [8].…”

Cinnoline Scaffold—A Molecular Heart of Medicinal Chemistry?

“…The phosphodiesterase 10A (PDE10A) enzyme is involved in cellular signaling pathways in schizophrenia. As a consequence, inhibitors of PDE10A offer a promising therapeutic approach for the treatment or prevention of psychiatric disorders, especially schizophrenia and related diseases [49].…”