ArticleJournal of medicinal chemistry2014
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.
Article in Journal of medicinal chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 45 citations in OpenAlex.
- Article
- Ectonucleotidase inhibitors: targeting signaling pathways for therapeutic advancement-an in-depth review.Purinergic signalling · 2025Review
- Double-modified, thio and methylene ATP analogue facilitates wound healing in vitro and in vivo.Scientific reports · 2024Article
- Article
- Stereocontrolled access to thioisosteres of nucleoside di- and triphosphates.Nature chemistry · 2024Article
- Small molecule innate immune modulators in cancer therapy.Frontiers in immunology · 2024Review
- AVA-NP-695 Selectively Inhibits ENPP1 to Activate STING Pathway and Abrogate Tumor Metastasis in 4T1 Breast Cancer Syngeneic Mouse Model.Molecules (Basel, Switzerland) · 2022Article
- Synthesis and Biological Evaluation of Arylamide Sulphonate Derivatives as Ectonucleotide Pyrophosphatase/Phosphodiesterase-1 and -3 Inhibitors.ACS omega · 2022Article
- Development of Novel Ecto-Nucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1) Inhibitors for Tumor Immunotherapy.International journal of molecular sciences · 2022Article
- Overview of Biologically Active Nucleoside Phosphonates.Frontiers in chemistry · 2020Review
- ENPP1, an Old Enzyme with New Functions, and Small Molecule Inhibitors-A STING in the Tale of ENPP1.Molecules (Basel, Switzerland) · 2019Review
- Review
- Identification of adenine-N9-(methoxy)ethyl-β-bisphosphonate as NPP1 inhibitor attenuates NPPase activity in human osteoarthritic chondrocytes.Purinergic signalling · 2019Article
- Review
- Substrate-Dependence of Competitive Nucleotide Pyrophosphatase/Phosphodiesterase1 (NPP1) Inhibitors.Frontiers in pharmacology · 2017Article
- A critical look at the function of the P2Y11 receptor.Purinergic signalling · 2016Review
Corrections and comments
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Authors and funding
12 authors at 4 institutions in 4 countries.
Funding
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-CH2-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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.