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

Molhm Nassir, Salahuddin Mirza, Uri Arad, Sangyong Lee, Muhammad Rafehi, Isaac Yaw Attah, Christian Renn, Herbert Zimmermann, Julie Pelletier, Jean Sévigny, Christa E. Müller, Bilha Fischer

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4 Scopus citations

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.

Original languageEnglish
Pages (from-to)9913-9923
Number of pages11
JournalOrganic and Biomolecular Chemistry
Volume17
Issue number46
DOIs
StatePublished - 2019

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© 2019 The Royal Society of Chemistry.

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