Nucleotide pyrophosphatase/phosphodiesterases (NPPs) including NPP1 and NPP2/ ATX as important drug targets: A patent review (2015-2020)

ABSTRACT

Introduction

Ectobucleotidases are a broad class of extracellular nucleotide and nucleoside hydrolyzing enzymes. Since they play a crucial role in mediating purinergic cell signalling, they are promising therapeutic targets for treatment of a range of disorders, including fibrosis, tumor metastasis, inflammation, multiple sclerosis, and autoimmune diseases. Hence selective inhibtors of ectonulceotidases are of great interest for therapeutic intervention.

Area covered

Many compounds have demonstrated promising inhibitory potential against ecto-nucleotide pyrophosphatase/phosphodiesterases (NPPs). The chemistry and clinical applications of NPP inhibitors patented between 2015 and 2020 are discussed in this review.

Expert opinion

In recent years, there has been a lot of effort towards finding effective and selective inhibitors of NPPs. Even though a number of inhibitors are known, only a few in vivo investigations have been published. In addition to IOA-289, which has passed Phase Ia clinical trials, potent NPP2/ATX inhibitor compounds such as BLD-0409, IPF and BBT-877 have been placed in phase I clinical studies. Some of the most promising NPP2/ATX inhibitors in recent years are closely related analogs of previously known inhibitors, such as PF-8380. Knowledge of the structure activity relationship of such promising inhibitors can potentially translate into the discovery of more potent and effective inhibitors of NPP.

KEYWORDS:

• Ecto-nucleotide pyrophosphatases/phosphodiesterases
• cancer
• inflammation
• inhibitors
• idiopathic pulmonary fibrosis

Article highlights

• The extracellular levels of nucleosides and nucleotides, that act as important cell-signaling molecules in purinergic cell signaling, are closely regulated by ectonucleotidase enzymes including nucleotide pyrophosphatases/phosphodiesterases (NPPs).

• Peculiar expression of NPPs has been found in several diseases including cell motility, cell migration, bone mineralization dysfunction, angiogenesis, type 2 diabetes, and tumor cell invasion.

• Synthetic inhibitors with variety of chemical structures have been discovered. However, so far, only a few studies on their in vivo efficacy have been published.

• Potent NPP2/ATX inhibitors BLD-0409, BBT-877 and IOA-289 have been registered in phase I clinical studies

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.