The Development of New Factor Xa Inhibitors Based on Amide Synthesis

Dmitry N Tarasov, Dmitry G Tovbin, Dmitry V Malakhov, Arseniy V Aybush, Natalia A Tserkovnikova, Marina I Savelyeva, Dmitry A Sychev, Natalia N Drozd, Alla Y Savchenko, Dmitry N Tarasov, Dmitry G Tovbin, Dmitry V Malakhov, Arseniy V Aybush, Natalia A Tserkovnikova, Marina I Savelyeva, Dmitry A Sychev, Natalia N Drozd, Alla Y Savchenko

Abstract

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.

Keywords: Chemical amide synthesis; a new direct factor Xa inhibitor; antithrombotic drug; direct oral anticoagulant; fibrinogen; thrombis formation..

Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Figures

Scheme 1
Scheme 1
General Synthetic Pathways. Reagents and conditions: (a) SOCl2, THF, reflux; (b) SnCl2, water, boiling; (c) methyl isocyanate, THF, room temperature; (d) EDCI, THF, room temperature; (e) TFAA, 0°C; (f) NaOH, isopropanol, room temperature; (g) NaHCO3, HCl, acetonitrile, 5°C.
Fig. (1)
Fig. (1)
The prothrombin time (PT) after per os administration of DD217 (3.3 mg/kg) in monkeys (axis X - the time after per os administration, h; axis Y - the ratio of the plasma coagulation time after per os administration PTmax to the plasma coagulation time before per os administration PT0, %).

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