Definition
ChEBI: Betrixaban is a secondary carboxamide obtained by formal condensation of the carboxy group of 4-(N,N-dimethylcarbamimidoyl)benzoic acid with the amino group of 2-amino-N-(5-chloropyridin-2-yl)-5-methoxybenzamide. A synthetic anticoagulant compound that targets activated factor Xa in the coagulation cascade. It has a role as an anticoagulant and an EC 3.4.21.6 (coagulation factor Xa) inhibitor. It is a member of guanidines, a member of benzamides, a secondary carboxamide, a monochloropyridine and a monomethoxybenzene.
Biological Activity
betrixaban is a highly potent, selective, and orally efficacious inhibitor of factor xa with ic50 value of 1.5nm [1].betrixaban shows excellent anticoagulant potency in vitro. in the rabbit deep vein thrombosis model, the concentration of betrixaban required to double the rabbit prothrombin time is below 2μm. betrixaban is selective for fxa and has poor activity for thrombin, trypsin, t-pa and apc. the patch clamp herg assay shows that betrixaban has low affinity with herg suggesting it is safer than other candidate compounds. in addition, betrixaban displays a profile of good oral bioavailability and oral exposure, long half-life in animal models. it has bioavailability of 51.6% at dose of 0.5 mg/kg iv and 2.5 mg/kg po. furthermore, the phase ii study has proved betrixaban as an oral fxa inhibitor for prevention of venous thromboembolic events [1].
in vivo
Betrixaban (0.5 mg/kg, i.v.; 2.5 mg/kg, p.o.) has oral bioavailability of 51.6% in dog[1].
Betrixaban (0.75 mg/kg, i.v.; 7.5 mg/kg, p.o.) has oral bioavailability of 58.7% in monkey[1].
Betrixaban mediated whole-blood INR increase is reversed by r-Antidote. After i.v. infusion for 30 min, the total plasma concentrations of Betrixaban is 0.2±0.01 μM, and the percentages of unbound inhibitor is 40%±7.2%. After administration of r-Antidote, the total plasma concentration increased to 2.0±0.4 μM, and the percentage of unbound inhibitor declined to 0.3%±0.1%[2].
Betrixaban (3 mg/kg) shows nearly comparable inhibition of thrombus mass to enoxaparin 1.6 mg/kg (76% vs 96% inhibition) in the rabbit abdominal vena cava model of clot accretion on cotton threads[3].
Betrixaban (19.1 mg/kg) is at least as effective at maintaining patency as enoxaparin 7.6 mg/kg and clopidogrel 3 mg/kg/d (90% vs 70% vs 80% patency, respectively) in the ferric chloride injury model of rodent carotid artery[3].
References
[1] zhang p, huang w, wang l, bao l, jia zj, bauer sm, goldman ea, probst gd, song y, su t, fan j, wu y, li w, woolfrey j, sinha u, wong pw, edwards st, arfsten ae, clizbe la, kanter j, pandey a, park g, hutchaleelaha a, lambing jl, hollenbach sj, scarborough rm, zhu by. discovery of betrixaban (prt054021), n-(5-chloropyridin-2-yl)-2-(4-(n,n-dimethylcarbamimidoyl)benzamido)-5-methoxybenzamide, a highly potent, selective, and orally efficacious factor xa inhibitor. bioorg med chem lett. 2009 apr 15;19(8):2179-85.
