Structure and pharmacokinetics/pharmacodynamics of the anticoagulant tetradecasaccharide oHG-14 as an intrinsic tenase inhibitor.

The intrinsic tenase complex (iXase) is an attractive antithrombotic target to treat or prevent pathological thrombosis with negligible bleeding risk. Fucosylated glycosaminoglycan (FG) is a promising anticoagulant by inhibiting iXase. A depolymerized FG (dHG-5) as an anticoagulant has been approved for clinical trials. Given that dHG-5 is a multi-component drug candidate consisting of a homologous series of oligosaccharides, it is difficult to predict a clear pharmacokinetics. Here, as a major oligosaccharide component, the tetradecasaccharide (oHG-14) was purified from dHG-5 and its structure was defined as L-Fuc 3S4S -α(1,3)-L-Δ4,5GlcA-α(1,3)-{D-GalNAc 4S6S -β(1,4)-[L-Fuc 3S4S -α(1,]3)-D-GlcA-β(1,3)-} 3 -D-GalNAc 4S6S -β(1,4)-[L-Fuc 3S4S -α(1,]3)-D-GlcA-ol. oHG-14 showed potent iXase inhibitory activity in vitro and antithrombotic effect in vivo comparable to dHG-5. After single subcutaneous administration of oHG-14 at 8, 14.4 and 32.4 mg/kg to rats, the absolute bioavailability was 71.6 %–80.9 % determined by the validated bioanalytical methods. The maximum concentration (C max) was 3.73, 8.07, and 11.95 μg/mL, respectively, and the time reaching C max (T max) was about 1 h. oHG-14 was mainly excreted by kidney as the parent compound with the elimination kinetics of first-order linear model. Anticoagulant activity of oHG-14 was positively correlated with its concentration in rat plasma. The pharmacokinetics/pharmacodynamics (PK/PD) of oHG-14 is similar to that of dHG-5. This study could provide supportive data for the clinical trial of dHG-5 and further development of pure oligosaccharide as an antithrombotic drug candidate. [Display omitted] • dHG-5 is a multi-component anticoagulant by inhibiting iXase in clinical trials. • A tetradecasaccharide oHG-14 with equal anti-iXase activity to dHG-5 is identified. • oHG-14 has predictable pharmacokinetics and is mainly excreted by kidney. • The PK/PD of oHG-14 supports pure oligosaccharide as an anticoagulant candidate. [ABSTRACT FROM AUTHOR]