Synthesis and biological activity of 2-alkylated deoxyadenosine bisphosphate derivatives as P2Y1 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 [P-33]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 la, revealing a potential electronic interaction highly favorable between triple bond orbitals and the P2Y(1) receptor at this position. (C) 2004 Published by Elsevier Ltd.