Quinazolin-4-piperidin-4-methyl sulfamide PC-1 inhibitors: Alleviating hERG interactions through structure based design

Patel, Snahel; Habeski, Wendy M.; Cheng, Alan C.; Cruz, Elisa De La; Loh, Christine; Kablaoui, Natasha M.

doi:10.1016/j.bmcl.2009.04.006

Cited by 50 publications

(45 citation statements)

References 21 publications

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“…In the present series of experiments, we documented that QPS1 and QPS2 were potent inhibitors of NPP1 with Ki of 0.06 μM (59.3 nM) and 0.11 μM (110.4 nM) respectively. Patel et al (2009) …”

Section: Inhibitors Of Npp1mentioning

confidence: 99%

“…The in vivo kinetics and resistance to hydrolysis of QPS derivatives remain to be investigated. Some of the QPS derivatives bind to the hERG potassium channel and thus may induce prolongation of the QT interval (Patel et al, 2009). QPS1 is a potent ligand of hERG, whereas QPS2 has the best ratio of NPP1 inhibition to hERG binding.…”

Section: Limitationsmentioning

confidence: 99%

“…For instance, ARL67156 (6-N, N-Diethyl-D-β, γ-dibromomethylene ATP trisodium salt) inhibits NPP1 but also significantly affects other ectonucleotidases (Levesque et al, 2007). Quinazoline-4-piperidine sulfamides (QPS) have been described as potent inhibitors of NPP1 (Patel et al, 2009). However, it is presently unknown whether these compounds are specific and have biological activities in cell culture models.…”

Section: Introductionmentioning

confidence: 99%

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Quinazoline‐4‐piperidine sulfamides are specific inhibitors of human NPP1 and prevent pathological mineralization of valve interstitial cells

Shayhidin

Forcellini

Boulanger

et al. 2015

British J Pharmacology

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Background and Purpose Ectonucleotide pyrophosphatase/PDE1 (NPP1) is an ectoenzyme, which plays a role in several disorders including calcific aortic valve disease (CAVD). So far, compounds that have been developed as inhibitors of NPP1 lack potency and specificity. Quinazoline‐4‐piperidine sulfamides (QPS) have been described as potent inhibitors of NPP1. However, their mode of inhibition as well as their selectivity and capacity to modify biological processes have not been investigated. Experimental Approach In the present series of experiments, we have evaluated the efficacy of two derivatives, QPS1‐2, in inhibiting human NPP1, and we have evaluated the effect of the most potent derivative (QPS1) on other ectonucleotidases as well as on the ability of this compound to prevent phosphate‐induced mineralization of human primary aortic valve interstitial cells (VICs). Key Results The QPS1 derivative is a potent (Ki 59.3 ± 5.4 nM) and selective non‐competitive inhibitor of human NPP1. Moreover, QPS1 also significantly inhibited the K121Q NPP1 gene variant (Ki 59.2 ± 14.5 nM), which is prevalent in the general population. QPS1 did not significantly alter the activity of other nucleotide metabolizing ectoenzymes expressed at the cell surface, namely NPP3, NTPDases (1–3), ecto‐5′‐nucleotidase and ALP. Importantly, QPS1 in the low micromolar range (≤10 μM) prevented phosphate‐induced mineralization of VICs and lowered the rise of osteogenic genes as expected for NPP1 inhibition. Conclusions and Implications We have provided evidence that QPS1 is a potent and selective non‐competitive inhibitor of NPP1 and that it prevented pathological mineralization in a cellular model.

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Section: Inhibitors Of Npp1mentioning

confidence: 99%

Section: Limitationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Quinazoline‐4‐piperidine sulfamides are specific inhibitors of human NPP1 and prevent pathological mineralization of valve interstitial cells

Shayhidin

Forcellini

Boulanger

et al. 2015

British J Pharmacology

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“…Recently a series of quinazolin-4-piperidin-4-ethyl sulfamide has been reported as NPP1 inhibitors [18]. However, it has high affinity binding to hERG potassium channels, which results in drug-induced QT prolongation [18].…”

Section: Introductionmentioning

confidence: 99%

“…However, it has high affinity binding to hERG potassium channels, which results in drug-induced QT prolongation [18].…”

Section: Introductionmentioning

confidence: 99%

Identification of Potent and Selective Human Ecto-Nucleotide Pyrophosphatase/ Phosphodiesterase-3 (hNPP3) Inhibitors

Iqbal¹

2011

TOEIJ

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NPP3 inhibitors are promising therapeutic agents due to their potential as anti-cancer, anti-metastatic and anti-neurodegenerative drugs. We have identified the first potent and selective inhibitors of human NPP3. We have also estimated the biochemical properties of the main NPP family members that can hydrolyse nucleotides using p-nitrophenyl-5'-thymidine monophosphate as substrate. K m values were found to be 20 ± 4 and 15 ± 6 M for human NPP1 and NPP3, respectively. Maximum velocity (V max ) values calculated for NPP1 and NPP3 were 12 ± 2 and 5 ± 1 nmol p-nitrophenol released/min/mg of crude protein, respectively. A series of benzothiazole derivatives and a series of 1,3,4-oxadiazole-2-thiones was tested on hNPP1 and hNPP3. Benzothiazoles were the most potent non competitive inhibitors of hNPP3 described to date. 1,3,4-oxadiazole-2-thiones were also identified as compounds which inhibited specifically NPP3 over NPP1. The most potent compound was further characterized and found to exhibit a non competitive mechanism of inhibition.

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Small molecule ectonucleotide pyrophosphatase/phosphodiesterase 1 inhibitors in cancer immunotherapy for harnessing innate immunity

Choi

2022

Bulletin Korean Chem Soc

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Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) was recently identified as a major hydrolase of an endogenous stimulator of interferon genes (STING) agonist, 2′,3′‐cyclic guanosine monophosphate–adenosine monophosphate (cGAMP). ENPP1 is a promising therapeutic target in cancer immunotherapy, in which the inhibition of ENPP1 enhances anticancer immunity via STING‐mediated innate immune activation. This review highlights the role of ENPP1 in innate immunity and the recent discovery of small molecule ENPP1 inhibitors as immunomodulators in cancer immunotherapy.

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Quinazolin-4-piperidin-4-methyl sulfamide PC-1 inhibitors: Alleviating hERG interactions through structure based design

Cited by 50 publications

References 21 publications

Quinazoline‐4‐piperidine sulfamides are specific inhibitors of human NPP1 and prevent pathological mineralization of valve interstitial cells

Quinazoline‐4‐piperidine sulfamides are specific inhibitors of human NPP1 and prevent pathological mineralization of valve interstitial cells

Identification of Potent and Selective Human Ecto-Nucleotide Pyrophosphatase/ Phosphodiesterase-3 (hNPP3) Inhibitors

Small molecule ectonucleotide pyrophosphatase/phosphodiesterase 1 inhibitors in cancer immunotherapy for harnessing innate immunity

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