Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 60, Issue 3, Pages 1060-1075Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.6b01460
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Funding
- Industrial Macromolecular Crystallography Association
- U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-06CH11357]
- Hauptman-Woodward Medical Research Institute
- Industrial Macromolecular Crystallography Association
- U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-06CH11357]
- Hauptman-Woodward Medical Research Institute
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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. 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 EC1.5x = 0.27 mu M) and excellent selectivity against the relevant blood coagulation enzymes.
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