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Title: Imidazopyridine- and Purine-Thioacetamide Derivatives: Potent Inhibitors of Nucleotide Pyrophosphatase/Phosphodiesterase 1 (NPP1)
Authors: Chang, Lei
Lee, Sang-Yong
Leonczak, Piotr
Rozenski, Jef
De Jonghe, Steven
Hanck, Theodor
Müller, Christa E
Herdewijn, Piet # ×
Issue Date: Dec-2014
Publisher: ACS Publications
Series Title: Journal of Medicinal Chemistry vol:57 issue:23 pages:10080-100
Abstract: Nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1) belongs to the family of ecto-nucleotidases, which control extracellular nucleotide, nucleoside, and (di)phosphate levels. To study the (patho)physiological roles of NPP1 potent and selective inhibitors with drug-like properties are required. Therefore, a compound library was screened for NPP1 inhibitors using a colorimetric assay with p-nitrophenyl 5'-thymidine monophosphate (p-Nph-5'-TMP) as an artificial substrate. This led to the discovery of 2-(3H-imidazo[4,5-b]pyridin-2-ylthio)-N-(3,4-dimethoxyphenyl)acetamide (5a) as a hit compound with a Ki value of 217 nM. Subsequent structure-activity relationship studies led to the development of purine and imidazo[4,5-b]pyridine analogues with high inhibitory potency (Ki values of 5.00 nM and 29.6 nM, respectively) when assayed with p-Nph-5'-TMP as a substrate. Surprisingly, the compounds were significantly less potent when tested versus ATP as a substrate, with Ki values in the low micromolar range. A prototypic inhibitor was investigated for its mechanism of inhibition and found to be competitive versus both substrates.
URI: 
ISSN: 0022-2623
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Medicinal Chemistry (Rega Institute)
× corresponding author
# (joint) last author

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