Background: Factor Xa (FXa) is known to play a central role in blood coagulation
cascade and considered to be one of the most attractive targets for oral anticoagulants
of new generation.
Objective: Our approach for the development of directly acting oral anticoagulants
(DOAC), FXa inhibitors was demonstrated in this work.
Method: Chemical synthesis is the base of our approach for the development of potential
inhibitors. In this work, the substances like R1-(CONH)-R2-(CONH)-R3 are being
developed, using previously described docking and screening methods, where R1, R2
and R3 are some chemical groups and (CONH) are amide bonds connecting R1, R2 and
R3. The direction of amide bond (CONH) could be arbitrary for R1, R2 and R2, R3.
Results: Chemical modifications were made in the frame of the results, taking into
account the structure of FXa, chemical synthesis capabilities, as well as patentability
of the target compounds. Subnanomolar potency of several developed compounds
was achieved. Several analyzers and various testing-suites have been used to measure
the concentration that doubled the prothrombin time (PTx2). Moreover, in human
plasma the PTx2 concentration of the compound 217 (DD217) turned out to be
80±20 nM. The compound efficacy has proved by in vivo assays including oral administrations
in rats, rabbits and monkeys.
Conclusion: The pharmacodynamic profile of DD217 for oral administration in
cynomolgus monkeys proves the efficacy of the compound, which makes it promising
for the future preclinical trials.