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

Autor: Shayhidin EE; Laboratoire d'Études Moléculaires des Valvulopathies (LEMV), Groupe de Recherche en Valvulopathies (GRV), Quebec Heart and Lung Institute/Research Center, Department of Surgery, Université Laval, QC, Canada., Forcellini E; Canada Research Chair in Organic and Medicinal Chemistry, PROTEO, Department of Chemistry, Université Laval, QC, Canada., Boulanger MC; Laboratoire d'Études Moléculaires des Valvulopathies (LEMV), Groupe de Recherche en Valvulopathies (GRV), Quebec Heart and Lung Institute/Research Center, Department of Surgery, Université Laval, QC, Canada., Mahmut A; Laboratoire d'Études Moléculaires des Valvulopathies (LEMV), Groupe de Recherche en Valvulopathies (GRV), Quebec Heart and Lung Institute/Research Center, Department of Surgery, Université Laval, QC, Canada., Dautrey S; Canada Research Chair in Organic and Medicinal Chemistry, PROTEO, Department of Chemistry, Université Laval, QC, Canada., Barbeau X; Department of Biochemistry, PROTEO, Laval University, QC, Canada., Lagüe P; Department of Biochemistry, PROTEO, Laval University, QC, Canada., Sévigny J; Department of Microbiology, Infectious Diseases and Immunology, Université Laval, Québec, QC, Canada.; Centre de recherche du CHU de Québec, Québec, QC, Canada., Paquin JF; Canada Research Chair in Organic and Medicinal Chemistry, PROTEO, Department of Chemistry, Université Laval, QC, Canada., Mathieu P; Laboratoire d'Études Moléculaires des Valvulopathies (LEMV), Groupe de Recherche en Valvulopathies (GRV), Quebec Heart and Lung Institute/Research Center, Department of Surgery, Université Laval, QC, Canada.
Jazyk: angličtina
Zdroj: British journal of pharmacology [Br J Pharmacol] 2015 Aug; Vol. 172 (16), pp. 4189-99. Date of Electronic Publication: 2015 Jul 08.
DOI: 10.1111/bph.13204
Abstrakt: 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.
(© 2015 The British Pharmacological Society.)
Databáze: MEDLINE
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