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Adenine-(methoxy)ethoxy-Pα,α-dithio–triphosphate efficaciously and potently inhibits pathologic calcium pyrophosphate deposition in osteoarthritic human chondrocytes

Abstract

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, 7-10. The latter were obtained in a facile two-step synthesis from adenine-(methoxy)ethanol. Among analogs 7-10, adenine-(methoxy)ethoxy-Pα,α-dithio–triphosphate, 8, 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, 8 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, 8 did not activate P2Y1,2,6 receptors. Analog 8 was not toxic to cultured chondrocytes at 100 µM. Therefore, 8 may be suitable for further development as a drug candidate for the treatment of CPPD arthritis and other NPP1-related diseases.

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Publication details

The article was received on 10 Oct 2019, accepted on 08 Nov 2019 and first published on 08 Nov 2019


Article type: Paper
DOI: 10.1039/C9OB02199J
Org. Biomol. Chem., 2019, Accepted Manuscript

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    Adenine-(methoxy)ethoxy-Pα,α-dithio–triphosphate efficaciously and potently inhibits pathologic calcium pyrophosphate deposition in osteoarthritic human chondrocytes

    M. Nassir, S. Mirza, U. Arad, S. Y. Lee, M. Rafehi, I. Yaw Attah, C. Renn, H. Zimmermann, J. Pelletier, J. Sevigny, C. E. Muller and B. Fischer, Org. Biomol. Chem., 2019, Accepted Manuscript , DOI: 10.1039/C9OB02199J

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