Ectonucleotidase inhibitors: an updated patent review (2017-2023)

The main enzymes that hydrolyzes nucleotides at the cell surface are nucleoside triphosphate diphosphohydrolases (NTPDases), ecto-nucleotide pyrophosphatases/phosphodiesterases (ENPPs), alkaline phosphatases (APs) and ecto-5'- nucleotidase (e5'NT, CD73) and by regulating the concentration of nucleotides at the cell surface, these enzymes have the potential to affect various conditions such as fibrosis, cancer metastasis, pruritus, inflammation, and autoimmune diseases. Thus, they represent a prospective therapeutic target.

A number of molecules, including nucleoside/nucleotide and non-nucleoside analogues, and bicyclic compounds, have shown strong potential as ectonucleotidase inhibitors. This review covers the chemistry and clinical uses of ectonucleotidase inhibitors patented between 2017 and 2023.

By binding to their specific P1 and P2 receptors at the cell surface, nucleosides and nucleotides regulate a number of pathophysiological events such as inflammation, fibrosis, cancer, and autoimmune diseases. Interestingly, these nucleotides can be hydrolyzed to nucleosides by several cell surface enzymes called ectonucleotidases. The development of small molecules that modulate ectonucleotidase activity is, therefore, of therapeutic value. This review provides valuable insights into recent advancements, including combination therapy and enhanced selectivity, which are poised to shape the future of ectonucleotidase inhibition through a comprehensive analysis of patents.