Phosphodiesterase 10 (PDE10) inhibitors: an updated patent review (2014-present)

ABSTRACT

Introduction: Phosphodiesterase 10 (PDE10) is one of at least 11 different PDE families, which are the enzymes that degrade adenosine 3′,5′-cyclic monophosphate (cAMP) and/or guanosine 3′,5′-cyclic monophosphate (cGMP) by hydrolyzing the phosphodiester bonds. Inhibition of PDE10A represents a molecular target in the treatment of conditions that would benefit from the increase of the level of cAMP and/or cGMP such as neurological and psychiatric disorders, cancer, and diabetes.

Areas covered: The present article reviews the patent literature on PDE10A inhibitors (PDE10AIs) from 2014 to present and PDE10AI chemotypes from different chemical classes: heteroaryl- and aryl-nitrogen-heterocyclic compounds, unsaturated nitrogen-heterocyclic compounds with specific substituents such as pyrazolopyrimidine, aryloxymethyl cyclopropane, pyridizinone, imidazopyridine, triazoles and imidazo[2,1-a]isoidole. The article presents the potency of PDE10AIs, their efficacy in animal models, and their clinical utility in the treatment of schizophrenia. Therapeutic patents for the treatment of cancers, precancerous conditions, and diabetes were also collected.

Expert opinion: Several potent PDE10AIs have been described so far; however, clinical trials have shown that without preclinical optimization, the benefit of PDE10AIs in the treatment of schizophrenia is confounded by a high placebo effect. Understanding of the requirements for PDE10AIs constitutes a challenging but promising field of drug discovery and development.

KEYWORDS:

• Cancer
• diabetes
• PDE10 inhibitors
• schizophrenia

Article highlights

• Phosphodiesterase 10 (PDE10) is an enzyme that degrade adenosine 3′,5′-cyclic monophosphate (cAMP) and/or guanosine 3′,5′-cyclic monophosphate (cGMP) by hydrolyzing the phosphodiester bonds.

• Inhibition of PDE10A represents a molecular target in the treatment of neurological and psychiatric disorders, cancer, and diabetes.

• Several potent PDE10AIs have been described.

• Clinical trials have shown that without preclinical optimization, the benefit of PDE10AIs in the treatment of schizophrenia is confounded by a high placebo effect.

• Understanding of the requirements for PDE10AIs constitutes a challenging but promising field of drug discovery and development.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by the National Science Centre, Poland, grant [2016/21/D/NZ7/01573].