title: Quinazoline-4-piperidine sulfamides are specific inhibitors of human NPP1 and prevent pathological mineralization of valve interstitial cells.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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).
  
  
  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
  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.
authors.affiliation: 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.
authors.forename: Elnur Elyar
authors.initials: EE
authors.lastname: Shayhidin
authors.affiliation: Canada Research Chair in Organic and Medicinal Chemistry, PROTEO, Department of Chemistry, Université Laval, QC, Canada.
authors.forename: Elsa
authors.initials: E
authors.lastname: Forcellini
authors.affiliation: 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.
authors.forename: Marie-Chloé
authors.initials: MC
authors.lastname: Boulanger
authors.affiliation: 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.
authors.forename: Ablajan
authors.initials: A
authors.lastname: Mahmut
authors.affiliation: Canada Research Chair in Organic and Medicinal Chemistry, PROTEO, Department of Chemistry, Université Laval, QC, Canada.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Dautrey
authors.affiliation: Department of Biochemistry, PROTEO, Laval University, QC, Canada.
authors.forename: Xavier
authors.initials: X
authors.lastname: Barbeau
authors.affiliation: Department of Biochemistry, PROTEO, Laval University, QC, Canada.
authors.forename: Patrick
authors.initials: P
authors.lastname: Lagüe
authors.affiliation: Department of Microbiology, Infectious Diseases and Immunology, Université Laval, Québec, QC, Canada.|Centre de recherche du CHU de Québec, Québec, QC, Canada.
authors.forename: Jean
authors.initials: J
authors.lastname: Sévigny
authors.affiliation: Canada Research Chair in Organic and Medicinal Chemistry, PROTEO, Department of Chemistry, Université Laval, QC, Canada.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Paquin
authors.affiliation: 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.
authors.forename: Patrick
authors.initials: P
authors.lastname: Mathieu
mesh_terms: D000328:Adult; D000818:Animals; D001021:Aortic Valve / Q000166:cytology; D017209:Apoptosis / Q000187:drug effects; D019556:COS Cells; D002522:Chlorocebus aethiops; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000494:pharmacology*
chemical_list: D011799:Quinazolines; D010727:Phosphoric Diester Hydrolases; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1; D011755:Pyrophosphatases