PDB 2RA0 deposited: 2007-09-14 modified: 2009-02-24
Title X-ray Structure of FXa in complex with 7-fluoroindazole
Authors Abad, M.C., Crysler, C.S., Damiano, B.P., Giardino, E.C., Lee, Y.K., Lu, T., Markotan, T., Maryanoff, B.E., McComsey, D.F., Milkiewicz, K.L., Ninan, N., Pan, W., Parks, D.J., Player, M.R., Thieu, T.V.
Structure factors resolution 2.3 rfactor 0.246 rfree 0.314
DPI 0.83 theoretical min: 0.36

We have developed a novel series of potent and selective factor Xa inhibitors that employ a key 7-fluoroindazolyl moiety. The 7-fluoro group on the indazole scaffold replaces the carbonyl group of an amide that is found in previously reported factor Xa inhibitors. The structure of a factor Xa cocrystal containing 7-fluoroindazole 51a showed the 7-fluoro atom hydrogen-bonding with the N-H of Gly216 (2.9 A) in the peptide backbone. Thus, the 7-fluoroindazolyl moiety not only occupied the same space as the carbonyl group of an amide found in prior factor Xa inhibitors but also maintained a hydrogen bond interaction with the protein's beta-sheet domain. The structure-activity relationship for this series was consistent with this finding, as the factor Xa inhibitory potencies were about 60-fold greater (DeltaDelta G approximately 2.4 kcal/mol) for the 7-fluoroindazoles 25a and 25c versus the corresponding indazoles 25b and 25d. Highly convergent synthesis of these factor Xa inhibitors is also described.

J.Med.Chem. 2008 Jan; 51(2):282-297 doi:10.1021/jm701217r

Cross References
Database source Identifier Description
ChEMBL Document CHEMBL1140716
PubMed 18159923 JMCMAR
Biomolecule Structure Assembly Serial Assembly Type Conformational State Chains Ligands Atoms
2RA0/1 2RA0 1 dimer 0 2 1 2085