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

Structure-activity relationship study of NPP1 inhibitors based on uracil-N1-(methoxy)ethyl-β-phosphate scaffold. Eur J Med Chem. 2019 Oct 04;184:111754 Authors: Nassir M, Pelletier J, Arad U, Arguin G, Khazanov N, Gendron FP, Sévigny J, Senderowitz H, Fischer B 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 chondrocy...
Source: European Journal of Medicinal Chemistry - Category: Chemistry Authors: Tags: Eur J Med Chem Source Type: research