Edoxaban (Lixiana), a direct inhibitor of Factor Xa (FXa) was approved
by the Minister of Health, Labor, and Welfare in Japan in April 2011 for the
prevention of venous thromboembolism (VTE) after major orthopedic
surgery.
Edoxaban inhibits hFXa with a Ki=0.56 nM. Edoxaban is a
weak inhibitor of thrombin Ki=6000 nM, has >10,000 fold selectivity
over other serine proteases in the coagulation cascade, and demonstrates
selectivity over trypsin and chymotrypsin. The synthesis of this class of FXa inhibitors begins with assembly of the diaminocyclohexane scaffold, cis-t-butyl((1R,2S,5S)-2-amino-5-(dimethylcarbamoyl)cyclohexyl)carbamate.
The free amine is coupled to the P1 group, 2-((5-chloropyridin-2-yl)
amino)-2-oxoacetic acid. The Boc protecting group on the amine of the scaffold is removed and the resulting free amine is coupled to the P4 group,
5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid.
