Imidazopyridine- and Purine-Thioacetamide Derivatives: Potent Inhibitors of Nucleotide Pyrophosphatase/Phosphodiesterase 1 (NPP1)
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- 作者：Lei Chang ; Sang-Yong Lee ; Piotr Leonczak ; Jef Rozenski ; Steven De Jonghe ; Theodor Hanck ; Christa E. M眉ller ; Piet Herdewijn
- 刊名：Journal of Medicinal Chemistry
- 出版年：2014
- 出版时间：December 11, 2014
- 年：2014
- 卷：57
- 期：23
- 页码：10080-10100
- 全文大小：813K
- ISSN：1520-4804
文摘
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鈥?thymidine monophosphate (p-Nph-5鈥?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鈥揳ctivity 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鈥?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.