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P.07 DEVELOPMENT OF NPP1 INHIBITORS AS POTENTIAL DRUGS FOR THE TREATMENT OF OSTEOARTHRITIS/CPPD DISEASE Molhm Nassir a , Uri Arad b , Sangyong Lee c , Salahuddin Mirza c , Christian Renn c , Xihuan Luo c , Christa E. Müller c , and Bilha Fischer a Department of Chemistry, Bar-Ilan University, Ramat-Gan 52900 Israel b Department of Rheumatology, Tel Aviv Medical Center and the Faculty of Medicine, Tel Aviv University, Tel Aviv, 6997801, Israel c PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, Bonn, Germany, Overproduction of extracellular pyrophosphate due to hydrolysis of ATP by NPP1 leads to deposition of pathological Ca 2 P 2 O 7 · H 2 O (CPPD) in cartilage, resulting in a degenerative joint disease (CPPD disease) which has no cure. We explored the hypothesis that NPP1 inhibitors may be therapeutic agents for CPPD disease by inhibiting the hydrolysis of ATP. Specifically, we synthesized ADP derivatives where either P α,β phosphate groups or only P β phosphate, are replaced by sulfonate groups, analogs 1 , and 2 , respectively. In addition, we prepared acyclic ADP and AMP analogs in which the primary alcohol was substituted by bis-phosphonate, analogs 3-4 and 5 - 7 , respectively. Finally, we prepared acyclic ATP/ADP P α,α dithio- phosphate analogs, 8-11, which are expected to exhibit high affinity to Zn(II) ions in the active-site of the enzyme, while avoiding a chiral center at P α -phosphate, and the waste of half of the nucleotide. The novel analogs have been evaluated for their inhibitory effect on NPP1 and their selectivity to NPP1 vs. NPP3. Finally, we evaluated the effect of the inhibitors to reduce the formation of PPi and consequently to reduce CPPD formation, in human chondrocytes. Analogs 8 and 9 are the most promising inhibitors with K i values of 300 nM, 330 nM, respectively vs. analog i previously reported as a selective NPP1 inhibitor, K i 685 nM. 10 µM analogs 10 and 11 demonstrate 100% inhibition of NPPase activity in human chondrocytes . Therefore, we suggest potent and selective inhibitors of NPP1 for lowering extracellular PP i levels in cartilage for preventing and treating OA/CPPD.