Ectonucleotidase inhibitors: a patent review (2011-2016)

Abstract

Ectonucleotidases are a broad family of metallo-ectoenzymes that are responsible for hydrolysing a variety of nucleotides to nucleosides, hence orchestrating the activation of P1 and P2 cell receptors via controlled release of nucleotides and nucleosides. Many disorders such as impaired calcification including aortic calcification, neurological and immunological disorders, platelet aggregation, cell proliferation and metastasis. are characterized by an increase in expression of these ectonucleotidases. Consequently, selective inhibitors of ectonucleotidases are required for therapeutic intervention. Area covered: Several classes of compounds such as purine, nucleotide derivatives (e.g., ARL67156) and monoclonal antibodies, have shown promising ectonucleotidase inhibitory potential. This review discusses chemistry and therapeutic applications of ectonucleotidase inhibitors patented from 2011 to 2016. Expert opinion: All eukaryotic cells express nucleotide and nucleoside receptors on their cell surface and are capable of releasing extracellular nucleotides. Ectonucleotidases are a broad family of metallo-ectoenzymes that hydrolyze a variety of nucleotides to nucleosides. These extracellular nucleotides and nucleosides are important cell signalling molecules and mediate a variety of (patho)physiological processes by acting upon their respective P1 and/or P2 receptors. Discovery of molecules that can selectively inhibit or activate ectonucleotidases is crucial from therapeutic point of view, since it allows human intervention into purinergic cell signalling, thereby allowing us to modulate related (patho)physiological processes as desired.

Purinergic signaling, DAMPs, and inflammation

“…This simplified picture has prompted many pharmaceutical and biotechnology companies to develop a large number of reagents, small molecule drugs or antibodies, targeting the P2Rs most likely involved in inflammation and cancer, i.e., the P2X7R and the adenosine A2AR and A2BR (6,25,30). Along this same line of thinking, reagents targeting ecto-nucleotidases to slow down ATP hydrolysis and adenosine generation have also been developed (2).…”

CD38+CD39+ NK cells associate with HIV disease progression and negatively regulate T cell proliferation

“…demonstrated that degradation of extracellular ATP or AMP by ectonucleotidases lead to the accumulation of deoxyATP, which prevent DNA synthesis by inhibiting ribonucleotide reductase ( 42 ). In subsequent experiments, inhibitors of CD39, CD38, and CD73 were added to reduce adenosine production and restore T cell proliferation ( 43 ). Damaged and stressed cells release NAD+, which are hydrolyzed in a stepwise manner to synthesize adenosine by CD38 and CD73 ( 44 ).…”

CD39-adenosinergic axis in renal pathophysiology and therapeutics

“…Initial studies using a commercially available (APT102) engineered human nucleoside triphosphate diphosphhydrolase-3 (CD39L3) in a canine model of arterial thrombosis were very encouraging [126]. Conversely, various inhibitors of ectonucleotidases patented during the past few years [127], and the availability of therapeutic antibodies that selectively inhibit CD73 [128], widened the scope for modulating the CD39-adenosinergic axis in experimental therapeutics.…”