Therapeutic Potentials of Ecto‐Nucleoside Triphosphate Diphosphohydrolase, Ecto‐Nucleotide Pyrophosphatase/Phosphodiesterase, Ecto‐5′‐Nucleotidase, and Alkaline Phosphatase Inhibitors

Abstract

The modulatory role of extracellular nucleotides and adenosine in relevance to purinergic cell signaling mechanisms has long been known and is an object of much research worldwide. These extracellular nucleotides are released by a variety of cell types either innately or as a response to patho-physiological stress or injury. A variety of surface-located ecto-nucleotidases (of four major types; nucleoside triphosphate diphosphohydrolases or NTPDases, nucleotide pyrophosphatase/phosphodiesterases or NPPs, alkaline phosphatases APs or ALPs, and ecto-5'-nucleotidase or e5NT) are responsible for meticulously controlling the availability of these important signaling molecules (at their respective receptors) in extracellular environment and are therefore crucial for maintaining the integrity of normal cell functioning. Overexpression of many of these ubiquitous ecto-enzymes has been implicated in a variety of disorders including cell adhesion, activation, proliferation, apoptosis, and degenerative neurological and immunological responses. Selective inhibition of these ecto-enzymes is an area that is currently being explored with great interest and hopes remain high that development of selective ecto-nucleotidase inhibitors will prove to have many beneficial therapeutic implications. The aim of this review is to emphasize and focus on recent developments made in the field of inhibitors of ecto-nucleotidases and to highlight their structure activity relationships wherever possible. Most recent and significant advances in field of NTPDase, NPP, AP, and e5NT inhibitors is being discussed in detail in anticipation of providing prolific leads and relevant background for research groups interested in synthesis of selective ecto-nucleotidase inhibitors.

Zinc deficiency causes delayed ATP clearance and adenosine generation in rats and cell culture models

“…The ectoenzymes are divided into five principal groups/enzymes (Fig. 1): the ectonucleotide triphosphate diphosphohydrolase (ENTPDase) family, the ectonucleotide pyrophosphatase/phosphodiesterase (ENPP) family, the ecto-5′-nucleotidase (NT5E, also known as CD73), the alkaline phosphatase (ALP) family, and prostatic acid phosphatase (PAP) 17,18,20,22 . Specifically, the ENTPDase-family proteins play pivotal roles in the hydrolysis of extracellular ATP to ADP and ADP to AMP 23 .…”

Ocular Purine Receptors as Drug Targets in the Eye

“…However, a range of other G protein-dependent and independent signaling mechanisms are associated with activation of ARs. 1 Nucleoside derivatives that activate ARs (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) are shown in Fig. 1, and AR antagonists (both nucleosides and nonnucleosides, 25-49) are shown in Fig.…”

Big opportunities for small molecules in immuno-oncology

“…For several of the examples cited above, small-molecule inhibitors of CD39 have been used as proof that CD39 is involved in the production of adenosine. However, these tool compounds have many shortcomings 108 . ARL 67176 and 8-butylthio-ATP are nucleotide analogues with marginal selectivity and potency, and although they have been used for in vivo experiments, the pharmacokinetic behaviour of these compounds is unknown 109,110 .…”