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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.

Author information

1
Department of Chemistry, Bar-Ilan University, Ramat-Gan, 52900, Israel.
2
Centre de Recherche du CHU de Québec - Université Laval, Pavillon CHUL, Québec city, QC, Canada.
3
Department of Rheumatology, Tel Aviv Medical Center and the Faculty of Medicine, Tel Aviv University, Tel Aviv, 6997801, Israel.
4
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.
5
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.
6
Department of Chemistry, Bar-Ilan University, Ramat-Gan, 52900, Israel. Electronic address: bilha.fischer@biu.ac.il.

Abstract

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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