Malovichko O. Synthesis and properties of RGD mimetics based on nitrogen containing heterocycles

It has been synthesized the novel RGDF mimetic on the base of 4-oxo-4-(piperazine-1-yl) butyric acid residue, which has demonstrated a high in vitro antiaggregative activity (IC50 = 3.5*10-8 M). On the base of this mimetic, it has been synthesized the “double prodrug” (ex vivo ID50 = 0.22 mg/kg). For the first time, the residues of 4-(1,2,3,4-tetrahydroisoquinoline-7-yl-amino)-4-oxobutyric and 3-[(1,2,3,4-tetrahydroisoquinoline-7-yl-amino)carbonyl]benzoic acids have been proposed for molecular design of RGDF mimetics as surrogates of RGD peptide Arg-Gly moiety, and 1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid residue – as arginyl bioisostere. Synthesized RGDF mimetics are potent GPIIb/IIIa antagonists (10-8 – 10-10 M). Indexes for the antiaggregative activity and affinity allow to consider 1,2,3,4-tetrahydroisoquinoline derivatives as prospective potent antiaggregative agents.