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The Development of New Factor Xa Inhibitors Based on Amide Synthesis

BACKGROUND: Factor Xa (FXa) is known to play a central role in blood coagulation cascade and considered to be one of the most attractive tar-gets for oral anticoagulants of new generation. OBJECTIVE: Our approach for the development of directly acting oral anticoagu-lants (DOAC), FXa inhibitors was...

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Autores principales: Tarasov, Dmitry N., Tovbin, Dmitry G., Malakhov, Dmitry V., Aybush, Arseniy V., Tserkovnikova, Natalia A., Savelyeva, Marina I., Sychev, Dmitry A., Drozd, Natalia N., Savchenko, Alla Y.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Bentham Science Publishers 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6142410/
https://www.ncbi.nlm.nih.gov/pubmed/29468977
http://dx.doi.org/10.2174/1570163815666180215114732
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author Tarasov, Dmitry N.
Tovbin, Dmitry G.
Malakhov, Dmitry V.
Aybush, Arseniy V.
Tserkovnikova, Natalia A.
Savelyeva, Marina I.
Sychev, Dmitry A.
Drozd, Natalia N.
Savchenko, Alla Y.
author_facet Tarasov, Dmitry N.
Tovbin, Dmitry G.
Malakhov, Dmitry V.
Aybush, Arseniy V.
Tserkovnikova, Natalia A.
Savelyeva, Marina I.
Sychev, Dmitry A.
Drozd, Natalia N.
Savchenko, Alla Y.
author_sort Tarasov, Dmitry N.
collection PubMed
description BACKGROUND: Factor Xa (FXa) is known to play a central role in blood coagulation cascade and considered to be one of the most attractive tar-gets for oral anticoagulants of new generation. OBJECTIVE: Our approach for the development of directly acting oral anticoagu-lants (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 meth-ods, 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 pa-tentability of the target compounds. Subnanomolar potency of several devel-oped 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.
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spelling pubmed-61424102018-11-30 The Development of New Factor Xa Inhibitors Based on Amide Synthesis Tarasov, Dmitry N. Tovbin, Dmitry G. Malakhov, Dmitry V. Aybush, Arseniy V. Tserkovnikova, Natalia A. Savelyeva, Marina I. Sychev, Dmitry A. Drozd, Natalia N. Savchenko, Alla Y. Curr Drug Discov Technol Article BACKGROUND: Factor Xa (FXa) is known to play a central role in blood coagulation cascade and considered to be one of the most attractive tar-gets for oral anticoagulants of new generation. OBJECTIVE: Our approach for the development of directly acting oral anticoagu-lants (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 meth-ods, 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 pa-tentability of the target compounds. Subnanomolar potency of several devel-oped 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. Bentham Science Publishers 2018-12 2018-12 /pmc/articles/PMC6142410/ /pubmed/29468977 http://dx.doi.org/10.2174/1570163815666180215114732 Text en © 2018 Bentham Science Publishers https://creativecommons.org/licenses/by-nc/4.0/legalcode This is an open access article licensed under the terms of the Creative Commons Attribution-Non-Commercial 4.0 International Public License (CC BY-NC 4.0) (https://creativecommons.org/licenses/by-nc/4.0/legalcode), which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.
spellingShingle Article
Tarasov, Dmitry N.
Tovbin, Dmitry G.
Malakhov, Dmitry V.
Aybush, Arseniy V.
Tserkovnikova, Natalia A.
Savelyeva, Marina I.
Sychev, Dmitry A.
Drozd, Natalia N.
Savchenko, Alla Y.
The Development of New Factor Xa Inhibitors Based on Amide Synthesis
title The Development of New Factor Xa Inhibitors Based on Amide Synthesis
title_full The Development of New Factor Xa Inhibitors Based on Amide Synthesis
title_fullStr The Development of New Factor Xa Inhibitors Based on Amide Synthesis
title_full_unstemmed The Development of New Factor Xa Inhibitors Based on Amide Synthesis
title_short The Development of New Factor Xa Inhibitors Based on Amide Synthesis
title_sort development of new factor xa inhibitors based on amide synthesis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6142410/
https://www.ncbi.nlm.nih.gov/pubmed/29468977
http://dx.doi.org/10.2174/1570163815666180215114732
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