Highly potent and selective ectonucleotide pyrophosphatase/ phosphodiesterase i inhibitors based on an adenosine 5′-(α or γ)-Thio-(α,β- or β,γ)-methylenetriphosphate scaffold

Yael Nadel, Joanna Lecka, Yocheved Gilad, Gal Ben-David, Daniel Förster, Georg Reiser, Sarah Kenigsberg, Jean Camden, Gary A. Weisman, Hanoch Senderowitz, Jean Sévigny, Bilha Fischer

Research output: Contribution to journalArticlepeer-review

Abstract

Aberrant nucleotide pyrophosphatase/phosphodiesterase-1 (NPP1) activity is associated with chondrocalcinosis, osteoarthritis, and type 2 diabetes. The potential of NPP1 inhibitors as therapeutic agents, and the scarceness of their structure-activity relationship, encouraged us to develop new NPP1 inhibitors. Specifically, we synthesized ATP-α-thio-β,γ-CH2 (1), ATP-α-thio-β,γ-CCl2 (2), ATP-α-CH 2-γ-thio (3), and 8-SH-ATP (4) and established their resistance to hydrolysis by NPP1,3 and NTPDase1,2,3,8 (<5% hydrolysis) (NTPDase = ectonucleoside triphosphate diphosphohydrolase). Analogues 1-3 at 100 μM inhibited thymidine 5′-monophosphate p-nitrophenyl ester hydrolysis by NPP1 and NPP3 by >90% and 23-43%, respectively, and only slightly affected (0-40%) hydrolysis of ATP by NTPDase1,2,3,8. Analogue 3 is the most potent NPP1 inhibitor currently known, Ki = 20 nM and IC50 = 0.39 μM. Analogue 2a is a selective NPP1 inhibitor with Ki = 685 nM and IC50 = 0.57 μM. Analogues 1-3 were found mostly to be nonagonists of P2Y1/P2Y2/P2Y11 receptors. Docking analogues 1-3 into the NPP1 model suggested that activity correlates with the number of H-bonds with binding site residues. In conclusion, we propose analogues 2a and 3 as highly promising NPP1 inhibitors.

Original languageEnglish
Pages (from-to)4677-4691
Number of pages15
JournalJournal of Medicinal Chemistry
Volume57
Issue number11
DOIs
StatePublished - 12 Jun 2014

All Science Journal Classification (ASJC) codes

  • Drug Discovery
  • Molecular Medicine

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