title: 8-BuS-ATP derivatives as specific NTPDase1 inhibitors.
abstract: OBJECTIVE
  Ectonucleotidases control extracellular nucleotide levels and consequently, their (patho)physiological responses. Among these enzymes, nucleoside triphosphate diphosphohydrolase-1 (NTPDase1), -2, -3 and -8 are the major ectonucleotidases responsible for nucleotide hydrolysis at the cell surface under physiological conditions, and NTPDase1 is predominantly located at the surface of vascular endothelial cells and leukocytes. Efficacious inhibitors of NTPDase1 are required to modulate responses induced by nucleotides in a number of pathological situations such as thrombosis, inflammation and cancer.
  
  
  METHODS
  Here, we present the synthesis and enzymatic characterization of five 8-BuS-adenine nucleotide derivatives as potent and selective inhibitors of NTPDase1.
  
  
  RESULTS
  The compounds 8-BuS-AMP, 8-BuS-ADP and 8-BuS-ATP inhibit recombinant human and mouse NTPDase1 by mixed type inhibition, predominantly competitive with Ki values <1 μM. In contrast to 8-BuS-ATP which could be hydrolyzed by other NTPDases, the other BuS derivatives were resistant to hydrolysis by either NTPDase1, -2, -3 or -8. 8-BuS-AMP and 8-BuS-ADP were the most potent and selective inhibitors of NTPDase1 expressed in human umbilical vein endothelial cells as well as in situ in human and mouse tissues. As expected, as a result of their inhibition of recombinant human NTPDase1, 8-BuS-AMP and 8-BuS-ADP impaired the ability of this enzyme to block platelet aggregation. Importantly, neither of these two inhibitors triggered platelet aggregation nor prevented ADP-induced platelet aggregation, in support of their inactivity towards P2Y1 and P2Y12 receptors.
  
  
  CONCLUSIONS
  The 8-BuS-AMP and 8-BuS-ADP have therefore potential to serve as drugs for the treatment of pathologies regulated by NTPDase1.
authors: Centre de recherche en Rhumatologie et Immunologie, Centre Hospitalier Universitaire (CHU) de Québec, Canada.
authors: Joanna
authors: J
authors: Lecka
authors: Irina
authors: I
authors: Gillerman
authors: Michel
authors: M
authors: Fausther
authors: Mabrouka
authors: M
authors: Salem
authors: Mercedes N
authors: MN
authors: Munkonda
authors: Jean-Philippe
authors: JP
authors: Brosseau
authors: Christine
authors: C
authors: Cadot
authors: Mireia
authors: M
authors: Martín-Satué
authors: Pedro
authors: P
authors: d'Orléans-Juste
authors: Eric
authors: E
authors: Rousseau
authors: Donald
authors: D
authors: Poirier
authors: Beat
authors: B
authors: Künzli
authors: Bilha
authors: B
authors: Fischer
authors: Jean
authors: J
authors: Sévigny
mesh_terms: D000244:Adenosine Diphosphate / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology*; D000249:Adenosine Monophosphate / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology*; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D015703:Antigens, CD; D001081:Apyrase / Q000037:antagonists & inhibitors*; D019556:COS Cells; D002522:Chlorocebus aethiops; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051379:Mice; D010974:Platelet Aggregation / Q000187:drug effects; D051381:Rats; D013045:Species Specificity
chemical_list: D015703:Antigens, CD; D004791:Enzyme Inhibitors; D000249:Adenosine Monophosphate; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D001081:Apyrase; C067869:CD39 antigen