Ectonucleotidase inhibitors: a patent review (2011-2016)

ABSTRACT

Introduction: 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.

KEYWORDS:

• Ectonucleotidase inhibitors
• purinergic cell signalling
• nucleotides
• nucleosides
• P1 and P2 receptors.

Article highlights

• Ectonucleotidases are a broad family of metal ion dependent nucleotide hydrolysing ectoenzymes that are at the epicenter of purinergic cell signalling, since they meticulously control the availability of various nucleotides and nucleosides at their respective receptors (P1 or P2), thereby indirectly orchestrating the activation of P1 and P2 receptors.

• Many physiological and pathophysiological processes, such as development, neuromodulation, nociception, blood flow, cell proliferation, and immunity, are regulated as a result of ectonucleotidase activity.

• Overexpression or hyperactivity of ectonucleotidases is responsible for many disorders, consequently inhibitors of ectonucleotidases are highly sought after for therapeutic intervention. However, the greatest challenge in the design of ectonucleotidase inhibitors is their selectivity/specificity. From therapeutic point of view, an ectonucleotidase inhibitor drug molecule should selectively act upon its specific target only, and should either (ideally) not inhibit other ectonucleotidases, or (less ideally) inhibit other ectonucleotidases to a significantly lesser extent.

• Although many classes of compounds such as anthraquinone (suramin) polyoxometalates, purine and nucleotide derivatives (e.g., ARL67156 among many others) and monoclonal antibodies, have shown promising ectonucleotidase inhibitory potential, it is crucial that new classes of compounds be screened for their potential to selectively inhibit ectonucleotidases.

• This review focuses specifically on the inhibitors of ectonucleotidases patented from 2011-2016, and their therapeutic applications.

This box summarizes key points contained in the article.

Declaration of interest

J Iqbal, M Al-Rashida, S Qazi, N Batool, A Hameed and S Ali received research grants from Higher Education Commission (HEC) Pakistan. 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.

Additional information

Funding

This paper was funded by Higher Education Commission, Pakistan Project Number 20-3733.