Imidazopyridine- and purine-thioacetamide derivatives: potent inhibitors of nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1).
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.
Interface Valorisation Platform, KU Leuven , Kapucijnenvoer 33, 3000 Leuven, Belgium.
Lei
L
Chang
Sang-Yong
SY
Lee
Piotr
P
Leonczak
Jef
J
Rozenski
Steven
S
De Jonghe
Theodor
T
Hanck
Christa E
CE
Müller
Piet
P
Herdewijn
D000081:Acetamides / Q000138:chemical synthesis; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D007093:Imidazoles / Q000138:chemical synthesis; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects; D011755:Pyrophosphatases / Q000037:antagonists & inhibitors*; D013853:Thioacetamide / Q000138:chemical synthesis*
D000081:Acetamides; D004791:Enzyme Inhibitors; D007093:Imidazoles; D013853:Thioacetamide; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases; C021899:nucleotide pyrophosphatase