The therapeutic potential of phosphodiesterase 9 (PDE9) inhibitors: a patent review (2018-present)

ABSTRACT

Introduction

Phosphodiesterase 9 (PDE9) has been demonstrated as a potential target for neurological disorders and cardiovascular diseases, such as Alzheimer’s disease and heart failure. For the last few years, a series of PDE9 inhibitors with structural diversities have been developed and patented by researchers and pharmaceutical companies, providing insights into first-in-class therapies of PDE9 drug candidates.

Area covered

This review provides an overview of PDE9 inhibitors in patents from 2018 to the present.

Expert opinion

Only a few of the current PDE9 inhibitors are highly selective over other PDEs, which limits their application in pharmacological and clinical research. The design and development of highly selective PDE9 inhibitors remain the top priority in future research. The advantages of targeting PDE9 rather than other PDEs in treating neurodegenerative diseases need to be explained thoroughly. Besides, application of PDE9 inhibitor-based combination therapies sheds light on treating diabetes and refractory heart diseases. Finally, PDE9 inhibitors should be further explored in clinical indications beyond neurological disorders and cardiovascular diseases.

KEYWORDS:

• Phosphodiesterase
• PDE9
• therapeutic targets
• Alzheimer’s disease
• heart failure

Article highlights

• PDE9 inhibitors spanning from 2018 to the present were classified by their chemical scaffolds in the review.

• Plenty of PDE9 inhibitors have been reported in the last few years, but highly selective ones are relatively few.

• The mechanism and benefits of targeting PDE9 in diseases such as neurological disorders require further elucidation.

• PDE9 inhibitors should be further explored in clinical indications beyond neurological disorders and cardiovascular diseases.

Acknowledgments

We cordially thank Prof. H. Ke from the Department of Biochemistry and Biophysics at the University of North Carolina, Chapel Hill, for his assistance with the molecular cloning, expression, purification, determination of the crystal structures, and bioassay of PDEs.

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.

Author contribution statement

C. Zhang: Writing – Original draft preparation, Reviewing and Editing, Visualization; Z.-H. Xue: Writing – Original draft preparation; W.-H. Luo: Writing – Original draft preparation; M.-Y. Jiang: Visualization; Y. Wu: Writing – Writing – Original draft preparation, Reviewing and Editing.

Additional information

Funding

This paper was funded by the Natural Science Foundation of China [82003652, 22377155, and 21977127].