3LC3

Benzothiophene Inhibitors of Factor IXa

Summary for 3LC3

• Entry DOI: 10.2210/pdb3lc3/pdb
• Related: 3LC5
• Descriptor: Coagulation factor IX, 1-[5-(3,4-dimethoxyphenyl)-1-benzothiophen-2-yl]methanediamine, CALCIUM ION, ... (5 entities in total)
• Functional Keywords: protein-inhibitor complex, peptidase s1, blood coagulation, calcium, cleavage on pair of basic residues, disease mutation, disulfide bond, egf-like domain, gamma-carboxyglutamic acid, glycoprotein, hemophilia, hydrolase, hydroxylation, pharmaceutical, phosphoprotein, polymorphism, protease, secreted, serine protease, sulfation, zymogen, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human); More
• Cellular location: Secreted: P00740 P00740
• Total number of polymer chains: 4
• Total formula weight: 66231.67

Authors

Wang, S.,Beck, R. (deposition date: 2010-01-09, release date: 2010-02-23, Last modification date: 2024-11-06)

Primary citation

Wang, S.,Beck, R.,Blench, T.,Burd, A.,Buxton, S.,Malic, M.,Ayele, T.,Shaikh, S.,Chahwala, S.,Chander, C.,Holland, R.,Merette, S.,Zhao, L.,Blackney, M.,Watts, A.
Studies of Benzothiophene Template as Potent Factor IXa (FIXa) Inhibitors in Thrombosis.
J.Med.Chem., 53:1465-1472, 2010

PubMed Abstract: FIXa is a serine protease enzyme involved in the intrinsic pathway of the coagulation cascade. The upstream intervention of the coagulation cascade in selectively inhibiting FIXa would leave hemostasis intact via the extrinsic pathway, leading to an optimum combination of efficacy and safety with low incidence of bleeding. We have identified 2-amindinobenzothiophene template as a lead scaffold for FIXa inhibiton based on its homology with urokinase plasminogen activator (uPA). Subsequent SAR work on the template revealed a number of highly potent FIXa inhibitors, though with moderate selectivity against FXa. X-ray study with one of the analogues demonstrated active site binding interaction with the induced opening of the S1 beta pocket and a secondary binding at the S2-S4 sites, which is in direct contrast with the previous finding.

PubMed: 20121198
DOI: 10.1021/jm901475e

Experimental method

X-RAY DIFFRACTION (1.9 Å)