SR123781A, a synthetic heparin mimetic

SR123781A, a synthetic hexadecasaccharide comprising an antithrombin (AT) b inding domain, a thrombin binding domain, and a neutral methylated hexasacc haride sequence, was obtained from glucose through a convergent synthesis. SR123781A showed high affinity for human AT (Kd = 58 +/- 22 nM) and was a p otent catalyst of its inhibitory effect with regard to factor Xa (IC50 = 77 +/- 5 ng/ml - 297 +/- 13 U/mg) and thrombin (IC50 = 4.0 +/- 0.5 ng/ml - 15 0 +/- 30 U/mg). SR123781A which acted exclusively via AT (no effect via hep arin cofactor II at a concentration of 6 mug/ml) inhibited thrombin generat ion occurring via both the extrinsic and intrinsic pathways in vitro in hum an plasma. SR123781A did not compete for H-3-heparin binding to PF4 and did not activate platelets in the presence of plasma from patients with hepari n-induced thrombocytopenia. After intravenous or subcutaneous administratio n to rats, rabbits or baboons. SR123781A displayed prolonged anti-factor Xa and anti-factor IIa activity ex vivo. After intravenous injection to baboo ns, decreases of the anti-factor Xa and anti-thrombin activities were paral lel and disappeared with the same pharmacodynamics. Intravenous administrat ions of SR123781A strongly inhibited thrombus formation in an experimental model of thromboplastin-induced venous thrombosis in rats with an ED50 valu e of 18 +/- 0.1 mug/kg (vs 77 +/- 3 mug/kg for heparin). SR123781A inhibite d arterial thrombus formation induced on a silk thread in an arterio-venous shunt and in the vena cava (ED50 values of 225 +/- 10 and 27 +/- 8 mug/kg, respectively). Compared to standard and low molecular weight heparin and t o presently used drugs, SR123781A exhibited a highly favourable anti-thromb otic/bleeding ratio therefore showing that it might be considered as a prom ising compound in the treatment and prevention of various thrombotic diseas es.