Download MendeleyStructure-Based Design of Macrocyclic Factor XIa Inhibitors: Discovery of the Macrocyclic Amide Linker.
Corte, J.R., Fang, T., Osuna, H., Pinto, D.J., Rossi, K.A., Myers, J.E., Sheriff, S., Lou, Z., Zheng, J.J., Harper, T.W., Bozarth, J.M., Wu, Y., Luettgen, J.M., Seiffert, D.A., Decicco, C.P., Wexler, R.R., Quan, M.L.(2017) J Med Chem 60: 1060-1075
- PubMed: 28085275
- DOI: https://doi.org/10.1021/acs.jmedchem.6b01460
- Primary Citation of Related Structures:
5TKS, 5TKT, 5TKU - PubMed 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. 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.
Organizational Affiliation:
Research and Development, Bristol-Myers Squibb Company , P.O. Box 5400, Princeton, New Jersey 08543, United States.
