8‐BuS‐ATP derivatives as specific NTPDase1 inhibitors

• Published in: British journal of pharmacology Vol. 169; no. 1; pp. 179 - 196
• Main Authors: Lecka, Joanna, Gillerman, Irina, Fausther, Michel, Salem, Mabrouka, Munkonda, Mercedes N, Brosseau, Jean‐Philippe, Cadot, Christine, Martín‐Satué, Mireia, d'Orléans‐Juste, Pedro, Rousseau, Éric, Poirier, Donald, Künzli, Beat, Fischer, Bilha, Sévigny, Jean
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.05.2013
• Subjects: adenine nucleotide analogue; Adenosine Diphosphate - analogs & derivatives; Adenosine Diphosphate - chemical synthesis; Adenosine Diphosphate - pharmacology; Adenosine Monophosphate - analogs & derivatives; Adenosine Monophosphate - chemical synthesis; Adenosine Monophosphate - pharmacology; Adenosine Triphosphate - analogs & derivatives; Adenosine Triphosphate - chemical synthesis; Adenosine Triphosphate - pharmacology; ADP; Animals; Antigens, CD; Apyrase - antagonists & inhibitors; ATP; Cercopithecus aethiops; COS Cells; ectoATPase; ectonucleotidase; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Human Umbilical Vein Endothelial Cells; Humans; inhibitors; Mice; Platelet Aggregation - drug effects; Rats; Research Papers; Species Specificity
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/bph.12135

Background and Purpose 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. Experimental Approach Here, we present the synthesis and enzymatic characterization of five 8‐BuS‐adenine nucleotide derivatives as potent and selective inhibitors of NTPDase1. Key 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 and Implications The 8‐BuS‐AMP and 8‐BuS‐ADP have therefore potential to serve as drugs for the treatment of pathologies regulated by NTPDase1.