Development of NPP1 inhibitors as potential drugs for the treatment of osteoarthritis/CPPD disease

Nucleotide pyrophosphatase/phosphodiesterase-1 (NPP1) inhibitors have been suggested as a potential treatment for calcium pyrophosphate dihydrate (CPPD) deposition disease. Here, we targeted the development of improved NPP1 inhibitors based on acyclic mimics of Pα,α-phosphorodithioate-substituted adenine nucleotides, 1-4. The latter were obtained in a facile two-step synthesis from adenine-(methoxy)ethanol. Among analogs 1-4, adenine-(methoxy)ethoxy-Pα,α-dithio–triphosphate, 2, was the most potent NPP1 inhibitor both with purified enzyme (IC50 0.645 µM) and in osteoarthritic human chondrocytes (IC50 0.033 µM). Furthermore, it efficaciously (10-fold vs. control) inhibited ATP-induced CPPD in human articular chondrocytes. Importantly, 2 was a highly selective NPP1 inhibitor which showed only minor inhibition of NPP3, CD39 and CD73, and did not inhibit TNAP (tissue nonspecific alkaline phosphatase) activity in human chondrocytes. Furthermore, 2 did not activate P2Y1,2,6 receptors. Analog 2 was not toxic to cultured chondrocytes at 100 µM. Therefore, 2 may be suitable for further development as a drug candidate for the treatment of CPPD arthritis and other NPP1-related diseases.

Fig. 1. Novel adenine nucleotide analogs developed here as NPP1 inhibitors.

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