Summary
PDB 3HPT deposited: 2009-06-04 modified: 2011-07-13
Title Crystal structure of human FxA in complex with (S)-2-cyano-1-(2-methylbenzofuran-5-yl)-3-(2-oxo-1-(2-oxo-2-(pyrrolidin-1-yl)ethyl)azepan-3-yl)guanidine
Authors Atwal, K.S., Bisaha, S.N., Chong, S., Hartl, K.S., Kish, K., Klei, H.E., Li, C., Liu, E.C., O'Connor, S.P., Pudzianowski, A.T., Schumacher, W.A., Seiler, S.M., Shi, M., Shi, Y., Sitkoff, D., Steinbacher, T.E., Stein, P.D., Yanchunas, J., Zhang, J.
Method X-RAY DIFFRACTION
Structure factors resolution 2.19 rfactor 0.17567 rfree 0.23868
DPI 0.47 theoretical min: 0.24
Citations

The N,N'-disubstituted cyanoguanidine is an excellent bioisostere of the thiourea and ketene aminal functional groups. We report the design and synthesis of a novel class of cyanoguanidine-based lactam derivatives as potent and orally active FXa inhibitors. The SAR studies led to the discovery of compound 4 (BMS-269223, K(i)=6.5nM, EC(2xPT)=32muM) as a selective, orally bioavailable FXa inhibitor with an excellent in vitro liability profile, favorable pharmacokinetics and pharmacodynamics in animal models. The X-ray crystal structure of 4 bound in FXa is presented and key ligand-protein interactions are discussed.

Bioorg.Med.Chem.Lett. 2009 Aug; 19(15):4034-4041 doi:10.1016/j.bmcl.2009.06.014

Cross References
Database source Identifier Description
ChEMBL Document CHEMBL1152385
PubMed 19541481 BMCLE8
Biomolecule Structure Assembly Serial Assembly Type Conformational State Chains Ligands Atoms
3HPT/1 3HPT 1 dimer 0 2 12 2565
3HPT/2 3HPT 2 dimer 0 2 11 2575