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

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.

doi:10.1021/acs.jmedchem.6b01460

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

Journal Article · Fri Jan 13 00:00:00 EST 2017 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/acs.jmedchem.6b01460· OSTI ID:1347764

^[1]; Fang, Tianan ^[1]; Osuna, Honey ^[1]; Pinto, Donald J. P. ^[1]; Rossi, Karen A. ^[1]; Myers, Joseph E. ^[1]; Sheriff, Steven ^[1]; Lou, Zhen ^[1]; Zheng, Joanna J. ^[1]; Harper, Timothy W. ^[1]; Bozarth, Jeffrey M. ^[1]; Wu, Yiming ^[1]; Luettgen, Joseph M. ^[1]; Seiffert, Dietmar A. ^[1]; Decicco, Carl P. ^[1]; Wexler, Ruth R. ^[1]; Quan, Mimi L. ^[1]

Bristol-Myers Squibb Company, Princeton, NJ (United States)

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 K_i = 0.16 nM with potent anticoagulant activity in an in vitro clotting assay (aPTT EC_1.5x = 0.27 μM) and excellent selectivity against the relevant blood coagulation enzymes.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1347764

Journal Information:: Journal of Medicinal Chemistry, Vol. 60, Issue 3; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 30 works

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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

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

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