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Title: Structure-Based Design of Macrocyclic Factor XIa Inhibitors: Discovery of the Macrocyclic Amide Linker

Abstract

A novel series of macrocyclic FXIa inhibitors was designed based on our lead acyclic phenyl imidazole chemotype. Our initial macrocycles, which were double-digit nanomolar FXIa inhibitors, were further optimized with assistance from utilization of structure-based drug design and ligand bound X-ray crystal structures. This effort resulted in the discovery of a macrocyclic amide linker which was found to form a key hydrogen bond with the carbonyl of Leu41 in the FXIa active site, resulting in potent FXIa inhibitors. Here, the macrocyclic FXIa series, exemplified by compound 16, had a FXIa Ki = 0.16 nM with potent anticoagulant activity in an in vitro clotting assay (aPTT EC1.5x = 0.27 μM) and excellent selectivity against the relevant blood coagulation enzymes.

Authors:
ORCiD logo [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1]
+ Show Author Affiliations
  1. Bristol-Myers Squibb Company, Princeton, NJ (United States)
Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES)
OSTI Identifier:
1347764
Grant/Contract Number:  
AC02-06CH11357
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Medicinal Chemistry
Additional Journal Information:
Journal Volume: 60; Journal Issue: 3; Journal ID: ISSN 0022-2623
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
ENGLISH
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; amides; peptides and proteins; phenyls; inhibitors; macrocycles; factor XIa; FXIa; factor XIa inhibitors; FXIa inhibitors; thrombosis; activated partial thromboplastin time; aPTT; anticoagulant; antithrombotic

Citation Formats

Corte, James R., Fang, Tianan, Osuna, Honey, Pinto, Donald J. P., Rossi, Karen A., Myers, Joseph E., Sheriff, Steven, Lou, Zhen, Zheng, Joanna J., Harper, Timothy W., Bozarth, Jeffrey M., Wu, Yiming, Luettgen, Joseph M., Seiffert, Dietmar A., Decicco, Carl P., Wexler, Ruth R., and Quan, Mimi L. Structure-Based Design of Macrocyclic Factor XIa Inhibitors: Discovery of the Macrocyclic Amide Linker. United States: N. p., 2017. Web. doi:10.1021/acs.jmedchem.6b01460.
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Corte, James R., Fang, Tianan, Osuna, Honey, Pinto, Donald J. P., Rossi, Karen A., Myers, Joseph E., Sheriff, Steven, Lou, Zhen, Zheng, Joanna J., Harper, Timothy W., Bozarth, Jeffrey M., Wu, Yiming, Luettgen, Joseph M., Seiffert, Dietmar A., Decicco, Carl P., Wexler, Ruth R., & Quan, Mimi L. Structure-Based Design of Macrocyclic Factor XIa Inhibitors: Discovery of the Macrocyclic Amide Linker. United States. https://doi.org/10.1021/acs.jmedchem.6b01460
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Corte, James R., Fang, Tianan, Osuna, Honey, Pinto, Donald J. P., Rossi, Karen A., Myers, Joseph E., Sheriff, Steven, Lou, Zhen, Zheng, Joanna J., Harper, Timothy W., Bozarth, Jeffrey M., Wu, Yiming, Luettgen, Joseph M., Seiffert, Dietmar A., Decicco, Carl P., Wexler, Ruth R., and Quan, Mimi L. Fri . "Structure-Based Design of Macrocyclic Factor XIa Inhibitors: Discovery of the Macrocyclic Amide Linker". United States. https://doi.org/10.1021/acs.jmedchem.6b01460. https://www.osti.gov/servlets/purl/1347764.
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@article{osti_1347764,
title = {Structure-Based Design of Macrocyclic Factor XIa Inhibitors: Discovery of the Macrocyclic Amide Linker},
author = {Corte, James R. and Fang, Tianan and Osuna, Honey and Pinto, Donald J. P. and Rossi, Karen A. and Myers, Joseph E. and Sheriff, Steven and Lou, Zhen and Zheng, Joanna J. and Harper, Timothy W. and Bozarth, Jeffrey M. and Wu, Yiming and Luettgen, Joseph M. and Seiffert, Dietmar A. and Decicco, Carl P. and Wexler, Ruth R. and Quan, Mimi L.},
abstractNote = {A novel series of macrocyclic FXIa inhibitors was designed based on our lead acyclic phenyl imidazole chemotype. Our initial macrocycles, which were double-digit nanomolar FXIa inhibitors, were further optimized with assistance from utilization of structure-based drug design and ligand bound X-ray crystal structures. This effort resulted in the discovery of a macrocyclic amide linker which was found to form a key hydrogen bond with the carbonyl of Leu41 in the FXIa active site, resulting in potent FXIa inhibitors. Here, the macrocyclic FXIa series, exemplified by compound 16, had a FXIa Ki = 0.16 nM with potent anticoagulant activity in an in vitro clotting assay (aPTT EC1.5x = 0.27 μM) and excellent selectivity against the relevant blood coagulation enzymes.},
doi = {10.1021/acs.jmedchem.6b01460},
journal = {Journal of Medicinal Chemistry},
number = 3,
volume = 60,
place = {United States},
year = {Fri Jan 13 00:00:00 EST 2017},
month = {Fri Jan 13 00:00:00 EST 2017}
}
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https://doi.org/10.1021/acs.jmedchem.6b01460
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