Highly Selective and Potent Ectonucleotide Pyrophosphatase-1 (NPP1) Inhibitors Based on Uridine 5′-P α,α -Dithiophosphate Analogues

Vadim Zelikman, Julie Pelletier, Luba Simhaev, Aviad Sela, Fernand Pierre Gendron, Guillaume Arguin, Hanoch Senderowitz, Jean Sévigny, Bilha Fischer

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19 Scopus citations


Ectonucleotide pyrophosphatase/phosphodiesterase-1 (NPP1) hydrolyzes phosphodiester bonds of nucleotides such as ATP, resulting mainly in the formation of AMP and pyrophosphate. NPP1 activity plays a deleterious function in calcified aortic valve disease and calcium pyrophosphate deposition disease. Thus, inhibitors of NPP1 represent a medical need. We developed novel NPP1 inhibitors based on uridine 5′-P α,α -dithiophosphate analogues, 9-12. All these analogues potently inhibited hNPP1 (80-100% inhibition) at 100 μM, with no, or minimal, inhibition of NPP3 and other ectonucleotidases (NTPDase1,2,3,8). These compounds showed nearly no activity at uracil-nucleotide sensitive P2Y 2,4,6 -receptors and thus represent highly selective NPP1 inhibitors. The most promising inhibitor was diuridine 5′-P α,α ,5″-P α,α -tetrathiotetraphosphate, 12, exhibiting K i of 27 nM. Analogues 9-12 proved to be highly stable to air oxidation and to acidic and basic pH. Docking simulations suggested that the enhanced NPP1 inhibitory activity and selectivity of analogue 12 could be attributed to the simultaneous occupancy of two sites (the AMP site and an alternative site) of NPP1 by this compound.

Original languageEnglish
Pages (from-to)3939-3951
Number of pages13
JournalJournal of Medicinal Chemistry
Issue number9
StatePublished - 10 May 2018

Bibliographical note

Funding Information:
J.S. received support from the Canadian Institutes of Health Research (CIHR), and he was the recipient of a Chercheur National research award from the Fonds de Recherche du Quebec, Sante (FRQS).

Publisher Copyright:
Copyright © 2018 American Chemical Society.


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