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Quinazoline‐4‐piperidine sulfamides are specific inhibitors of human NPP 1 and prevent pathological mineralization of valve interstitial cells
Author(s) -
Shayhidin Elnur Elyar,
Forcellini Elsa,
Boulanger MarieChloé,
Mahmut Ablajan,
Dautrey Sébastien,
Barbeau Xavier,
Lagüe Patrick,
Sévigny Jean,
Paquin JeanFrançois,
Mathieu Patrick
Publication year - 2015
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13204
Subject(s) - chemistry , pharmacology , population , biochemistry , medicine , environmental health
Background and Purpose Ectonucleotide pyrophosphatase/ PDE 1 ( NPP 1) 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 NPP 1 lack potency and specificity. Quinazoline‐4‐piperidine sulfamides ( QPS ) have been described as potent inhibitors of NPP 1. 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, QPS 1‐2, in inhibiting human NPP 1, and we have evaluated the effect of the most potent derivative ( QPS 1) 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 QPS 1 derivative is a potent (K i 59.3 ± 5.4 nM) and selective non‐competitive inhibitor of human NPP 1. Moreover, QPS 1 also significantly inhibited the K121Q NPP 1 gene variant (K i 59.2 ± 14.5 nM), which is prevalent in the general population. QPS 1 did not significantly alter the activity of other nucleotide metabolizing ectoenzymes expressed at the cell surface, namely NPP 3, NTPD ases (1–3), ecto‐5′‐nucleotidase and ALP . Importantly, QPS 1 in the low micromolar range (≤10 μM) prevented phosphate‐induced mineralization of VICs and lowered the rise of osteogenic genes as expected for NPP 1 inhibition. Conclusions and Implications We have provided evidence that QPS 1 is a potent and selective non‐competitive inhibitor of NPP 1 and that it prevented pathological mineralization in a cellular model.

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