3HPT

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

Summary for 3HPT

• Entry DOI: 10.2210/pdb3hpt/pdb
• Descriptor: Coagulation factor X, GLYCEROL, 1-cyano-2-(2-methyl-1-benzofuran-5-yl)-3-[(3S)-2-oxo-1-(2-oxo-2-pyrrolidin-1-ylethyl)azepan-3-yl]guanidine, ... (10 entities in total)
• Functional Keywords: serine protease, hydrolase, epidermal growth factor like domain, blood coagulation factor, cleavage on pair of basic residues, egf-like domain, gamma-carboxyglutamic acid, glycoprotein, hydroxylation, zymogen, blood clotting, blood coagulation, disulfide bond, protease, secreted
• Biological source: Homo sapiens (human); More
• Cellular location: Secreted: P00742 P00742
• Total number of polymer chains: 4
• Total formula weight: 76648.65

Authors

Klei, H.E.,Ghosh, K.,Rushith, A.,Kish, K. (deposition date: 2009-06-04, release date: 2009-11-17, Last modification date: 2024-10-09)

Primary citation

Shi, Y.,Zhang, J.,Shi, M.,O'Connor, S.P.,Bisaha, S.N.,Li, C.,Sitkoff, D.,Pudzianowski, A.T.,Chong, S.,Klei, H.E.,Kish, K.,Yanchunas, J.,Liu, E.C.,Hartl, K.S.,Seiler, S.M.,Steinbacher, T.E.,Schumacher, W.A.,Atwal, K.S.,Stein, P.D.
Cyanoguanidine-based lactam derivatives as a novel class of orally bioavailable factor Xa inhibitors.
Bioorg.Med.Chem.Lett., 19:4034-4041, 2009

PubMed Abstract: 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.

PubMed: 19541481
DOI: 10.1016/j.bmcl.2009.06.014

Experimental method

X-RAY DIFFRACTION (2.19 Å)