SR 90107A Org 31540, a novel anti-factor Xa antithrombotic agent

SR 90107A/Org 31540 is a new sulphated pentasaccharide obtained by total chemical synthesis. It is chemically identical with the antithrombin III (AT-III) binding site of heparin and heparan sulfate. SR 90107A/(Org 31540 showed high affinity for AT-III of various animal species including humans and exerted a strong anticoagulant effect because the complex of AT-III with SR 90107A/Org 31540-inactivated factor Xa is about 300 times more potent than free or uncomplexed AT-III. In several experimental thrombosis models in rats, rabbits and baboons, SR 90107A/Org 31540 displayed a potent antithrombotic activity by virtue of the specific and selective potentiation of factor Xa inhibitory activity of AT-III. This pentasaccharide caused only minimal and limited bleeding enhancement and did not affect platelet functions. Its bioavailability after s.c. administration to rats, rabbits and baboons, based on its anti-factor Xa activity, was 80 to 100%. Safety, tolerance and pharmacokinetics were investigated in healthy young adult and elderly subjects at two single rising dose studies over a dose range of 0.35 to 30 mg. Safety, tolerance, and effect kinetics were also investigated in a repeated rising dose study in healthy elderly subjects for 7 days, The drug was well tolerated and, at the highest doses the bleeding time was normal. Plasma peak anti-Xa levels and AUC were linearly related to the dose up to 24 mg (16,000 U) and ranged from 0.12 to 2.1 U/m1(0.18 to 3.23 μg/ml). The elimination half-life was approximately 15 h, independent of the dose. During these phase I clinical studies the clinical tolerance of SR 90107A/Org 31540 was good, suggesting that it might constitute a promising compound for the treatment and prevention of various thrombotic diseases.