Synthesis and biological activity of 2-alkylated deoxyadenosine bisphosphate derivatives as P2Y(1) receptor antagonists.
A previous study around adenine nucleotides afforded the reference N(6)-methyl-2'-deoxyadenosine-3',5'-bisphosphate (1a, MRS 2179) as a selective human P2Y(1) receptor antagonist (pA(2)=6.55+/-0.05) with antithrombotic properties. In the present paper, we have synthesized and tested in vitro various 2-substituted derivatives with the goal of exploring the 2-position binding region and developing more potent P2Y(1) receptor antagonists. Thus, we have adopted a novel and versatile chemical pathway using a palladium-catalyzed cross-coupling reaction with the 2-iodinated derivative 7 as a common intermediate for a very efficient synthesis of the 2-alkyl-N(6)-methyl-2'-deoxyadenosine-3',5'-bisphosphate nucleotides 1e-i. The biological activity was evaluated through the ability of compounds to inhibit ADP-induced platelet aggregation, intracellular calcium rise and to displace the specific binding of [(33)P]2-MeSADP. 2-Ethyl and 2-propyl groups appeared to be tolerated, whereas a bulky group or a C(3) linear substituent dramatically decreased potency of antagonists. The 2-ethynyl derivative 1h (pA(2)=7.54+/-0.10) was significantly more potent (10-fold) as an antagonist when compared to the reference 1a, revealing a potential electronic interaction highly favorable between triple bond orbitals and the P2Y(1) receptor at this position.
Mathieu
Romain
R
Laboratoire de Pharmacochimie de la Communication Cellulaire (CNRS, UMR 7081), Faculté de Pharmacie, Université Louis Pasteur, 74 route du Rhin, BP24, 67401 Illkirch cedex, France.
Baurand
Anthony
A
Schmitt
Martine
M
Gachet
Christian
C
Bourguignon
Jean-Jacques
JJ
D000244:Adenosine Diphosphate / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism; D001667:Binding, Competitive / Q000187:drug effects; D001792:Blood Platelets / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D003838:Deoxyadenine Nucleotides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors; D015394:Molecular Structure; D010165:Palladium / Q000737:chemistry; D010974:Platelet Aggregation / Q000187:drug effects; D058919:Purinergic P2 Receptor Antagonists; D058472:Receptors, Purinergic P2Y1; D058925:Receptors, Purinergic P2Y12; D013329:Structure-Activity Relationship
D000067956:Adenylyl Cyclase Inhibitors; D003838:Deoxyadenine Nucleotides; D008565:Membrane Proteins; C111914:N(6)-methyl-2'-deoxyadenosine 3',5'-diphosphate; C546382:P2RY1 protein, human; C548576:P2RY12 protein, human; D058919:Purinergic P2 Receptor Antagonists; D058472:Receptors, Purinergic P2Y1; D058925:Receptors, Purinergic P2Y12; C018891:deoxyadenosine diphosphate; D010165:Palladium; D000244:Adenosine Diphosphate; D000262:Adenylyl Cyclases; D002118:Calcium