Imidazopyridine- and Purine-Thioacetamide Derivatives: Potent Inhibitors of Nucleotide Pyrophosphatase/Phosphodiesterase 1 (NPP1)

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.

Medicinal chemistry of adenosine, P2Y and P2X receptors

“…These nucleotides are generally short-lived in the body, and thus the interconversion (including enzymatically mediated formation and deactivation) of P2YR agonists in situ has been a complicating factor from the outset of studies of P2YRs and purine/pyrimidine receptors in general. Various inhibitors of enzymes that process extracellular nucleotides have been reported recently (Bhattarai et al, 2015; Lee et al, 2015; Chang et al, 2014; Al-Rashida and Iqbal, 2014; Baqi, 2015; Corbelini et al, 2015), according to the strategy that the activation of P2Rs (and ARs) can be modulated effectively by indirect means (Zimmermann et al, 2012). …”

Synthesis of carbon-11-labeled imidazopyridine- and purine-thioacetamide derivatives as new potential PET tracers for imaging of nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1)

“…Compounds 4a and 8a have been reported previously. 1 They are potent NPP1 inhibitors with high inhibitory potency, and the K i values for 4a and 8a are 29.6 nM and 5.00 nM, respectively. 1 Reference standards 4a and 8a and their corresponding precursors…”

“…2 Overexpression of NPP1 is associated with a wide variety of diseases like type 2 diabetes, calcium pyrophosphate dehydrate deposition disease leading to inflammatory arthritis and brain cancers, and thus NPP1 has been proposed as a novel therapeutic protein target, and many NPP1 inhibitors have been developed for this purpose. [1][2][3][4][5] Recently a new class of imidazopyridineand purine-thioacetamide derivatives has been developed as potent and selective NPP1 inhibitors. 1 NPP1 has also become a promising target for molecular imaging of NPP1-related diseases and image-guided therapy using positron emission tomography (PET) modality.…”

“…[1][2][3][4][5] Recently a new class of imidazopyridineand purine-thioacetamide derivatives has been developed as potent and selective NPP1 inhibitors. 1 NPP1 has also become a promising target for molecular imaging of NPP1-related diseases and image-guided therapy using positron emission tomography (PET) modality. However, radionuclides including carbon-11 and fluorine-18 labeled NPP1 inhibitors are still not reported.…”

“…To meet investigator needs within our institution for PET imaging of diabetes, we are interested in tracer development and production. In our previous work, we have redeveloped [ 11 C]acetate-PET and [ 11 C]palmitate-PET to study cardiometabolic response and free fatty acid levels; and carbon-11labeled 4-(phenylamino)-pyrrolo[2,1-f] [1,2,4]triazine derivatives for imaging of p38 mitogen-activated protein kinase (MAPK) in diabetes, as indicated in Figure 1. [6][7][8][9] In this ongoing study, we first target NPP1 and develop radiolabeled NPP1 inhibitors.…”