3M37

Factor XA in complex with the inhibitor 1-[2-(aminomethyl)phenyl]-N-(3-fluoro-2'-sulfamoylbiphenyl-4-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (DPC602)

3M37 の概要

• エントリーDOI: 10.2210/pdb3m37/pdb
• 関連するPDBエントリー: 3M35 3M36
• 分子名称: Coagulation factor X, 1-[2-(aminomethyl)phenyl]-N-(3-fluoro-2'-sulfamoylbiphenyl-4-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide, CALCIUM ION, ... (5 entities in total)
• 機能のキーワード: glycoprotein, hydrolase, serine protease, plasma, blood coagulation factor, protein inhibitor complex, calcium- binding, blood coagulation, cleavage on pair of basic residues, disulfide bond, egf-like domain, gamma-carboxyglutamic acid, polymorphism, protease, secreted, zymogen
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Secreted: P00742 P00742
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 32609.91

構造登録者

Alexander, R.S. (登録日: 2010-03-08, 公開日: 2010-04-21, 最終更新日: 2024-11-27)

主引用文献

Pruitt, J.R.,Pinto, D.J.P.,Galemmo, R.A.Jr.,Alexander, R.S.,Rossi, K.A.,Wells, B.L.,Drummond, S.,Bostrom, L.L.,Burdick, D.,Bruckner, R.,Chen, H.,Smallwood, A.,Wong, P.C.,Wright, M.R.,Bai, S.,Luettgen, J.M.,Knabb, R.M.,Lam, P.Y.S.,Wexler, R.R.
Discovery of 1-(2-Aminomethylphenyl)-3-trifluoromethyl-N-[3-fluoro-2'-(aminosulfonyl)[1,1'-biphenyl)]-1H-pyrazole-5-carboxyamide (DPC602), a Potent, Selective, and Orally Bioavailable Factor Xa Inhibitor.
J.Med.Chem., 46:5298-5315, 2003

PubMed Abstract: Factor Xa, a serine protease, is at the critical juncture between the intrinsic and extrinsic pathways of the coagulation cascade. Inhibition of factor Xa has the potential to provide effective treatment for both venous and arterial thrombosis. We recently described a series of meta-substituted phenylpyrazoles that are highly potent, selective, and orally bioavailable factor Xa inhibitors. In this paper we report our efforts to further optimize the selectivity profile of our factor Xa inhibitors with a series of ortho- and/or para-substituted phenylpyrazole derivatives. The most potent compounds display sub-nanomolar inhibition constants for factor Xa and show greater than 1000-fold selectivity against other serine proteases. These compounds are also effective in a rabbit model of arteriovenous shunt thrombosis. Optimization of this series led to the preclinical development of DPC602, a 2-(aminomethyl)phenylpyrazole analogue, as a highly potent, selective, and orally bioavailable factor Xa inhibitor.

PubMed: 14640539

実験手法

X-RAY DIFFRACTION (1.9 Å)