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Eur J Med Chem. 2019 Dec 15;184:111754. doi: 10.1016/j.ejmech.2019.111754. Epub 2019 Oct 4.

Structure-activity relationship study of NPP1 inhibitors based on uracil-N1-(methoxy)ethyl-β-phosphate scaffold.

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Department of Chemistry, Bar-Ilan University, Ramat-Gan, 52900, Israel.
Centre de Recherche du CHU de Québec - Université Laval, Pavillon CHUL, Québec city, QC, Canada.
Department of Rheumatology, Tel Aviv Medical Center and the Faculty of Medicine, Tel Aviv University, Tel Aviv, 6997801, Israel.
Département d'immunologie et de biologie cellulaire, Faculté de Médecine et des sciences de la santé, Université de Sherbrooke, PRAC, 3201, Jean-Mignault, Sherbrooke, QC, J1E 4K8, Canada.
Centre de Recherche du CHU de Québec - Université Laval, Pavillon CHUL, Québec city, QC, Canada; Département de Microbiologie-Infectiologie et d'Immunologie, Faculté de Médecine, Université Laval, Quebec city, QC G1V 4G2, Canada.
Department of Chemistry, Bar-Ilan University, Ramat-Gan, 52900, Israel. Electronic address:


Overexpression of ecto-nucleotide pyrophosphatase-1 (NPP1) is associated with diseases such as calcium pyrophosphate dihydrate deposition disease, calcific aortic valve disease, and type 2 diabetes. In this context, NPP1 inhibitors are potential drug candidates for the treatment of these diseases. The present study focuses on the analysis of the structure-activity relationship of NPP1 inhibitors based on acyclic uracil-nucleotides. For this purpose, we synthesized acyclic uridine-monophosphate analogs, 10-11, uridine-diphosphate analogs, 12-14, and uridine-Pα,α-dithio-triphosphate analogs, 15-17. We evaluated their inhibitory activity and selectivity towards NPP1, -3, NTPDase1, -2, -3, and -8, and P2Y2,4,6 receptors. Analogs 16 and 17 were the most selective and potent NPP1 inhibitors (Ki 0.94 and 0.73 μM, respectively) among the tested molecules. Analogs 10-17 had only minute effect on uracil-nucleotide responding P2Y2,4,6 receptors. Analog 17 (100 μM) displayed 96% inhibition of NPPase activity in osteoarthritic human chondrocytes. Analogs 14-17 displayed weak inhibitory effect on alkaline phosphatase activity at equimolar concentrations in human chondrocytes. All tested analogs showed no toxicity at human chondrocytes. We concluded that ribose-ring to chain transformation, as well as the type of the nucleobase, are parameters of minor significance to NPP1 inhibition, whereas the major parameter is Pα-dithio-substitution. In addition, the length of the phosphate chain also significantly affects inhibition. Overall, the experimental results were well reproduced by molecular docking. A correlation was observed between the activities of the compounds and the number of H-bonds and salt bridges formed between the inhibitors and NPP1 binding site residues. Uracil-N1-(methoxy)ethyl-β-Pα,α-dithio, Pβ,γ-methylene tri-phosphate, 17, was identified as the most potent, selective, and non-toxic NPP1 inhibitor among the tested analogs, and may be used as a lead structure for further drug development.

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