5QCM

FACTOR XIA IN COMPLEX WITH THE INHIBITOR methyl ~{N}-[4-[[(1~{S})-2-[(~{E})-3-[3-chloranyl-2-fluoranyl-6-(1,2,3,4-tetrazol-1-yl)phenyl]prop-2-enoyl]-3,4-dihydro-1~{H}-isoquinolin-1-yl]carbonylamino]phenyl]carbamate

5QCM の概要

• エントリーDOI: 10.2210/pdb5qcm/pdb
• Group deposition: FXIa (G_1002041)
• 関連するPDBエントリー: 5QCK 5QCL 5QCN
• 分子名称: Coagulation factor XI, methyl ~{N}-[4-[[(1~{S})-2-[(~{E})-3-[3-chloranyl-2-fluoranyl-6-(1,2,3,4-tetrazol-1-yl)phenyl]prop-2-enoyl]-3,4-dihydro-1~{H}-isoquinolin-1-yl]carbonylamino]phenyl]carbamate, SULFATE ION, ... (5 entities in total)
• 機能のキーワード: hydrolase, serine protease, blood coagulation factor, protein inhibitor complex, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Secreted: P03951
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 29203.40

構造登録者

Sheriff, S. (登録日: 2017-08-10, 公開日: 2017-11-08, 最終更新日: 2026-02-18)

主引用文献

Pinto, D.J.P.,Orwat, M.J.,Smith, L.M.,Quan, M.L.,Lam, P.Y.S.,Rossi, K.A.,Apedo, A.,Bozarth, J.M.,Wu, Y.,Zheng, J.J.,Xin, B.,Toussaint, N.,Stetsko, P.,Gudmundsson, O.,Maxwell, B.,Crain, E.J.,Wong, P.C.,Lou, Z.,Harper, T.W.,Chacko, S.A.,Myers, J.E.,Sheriff, S.,Zhang, H.,Hou, X.,Mathur, A.,Seiffert, D.A.,Wexler, R.R.,Luettgen, J.M.,Ewing, W.R.
Discovery of a Parenteral Small Molecule Coagulation Factor XIa Inhibitor Clinical Candidate (BMS-962212).
J. Med. Chem., 60:9703-9723, 2017

PubMed Abstract: Factor XIa (FXIa) is a blood coagulation enzyme that is involved in the amplification of thrombin generation. Mounting evidence suggests that direct inhibition of FXIa can block pathologic thrombus formation while preserving normal hemostasis. Preclinical studies using a variety of approaches to reduce FXIa activity, including direct inhibitors of FXIa, have demonstrated good antithrombotic efficacy without increasing bleeding. On the basis of this potential, we targeted our efforts at identifying potent inhibitors of FXIa with a focus on discovering an acute antithrombotic agent for use in a hospital setting. Herein we describe the discovery of a potent FXIa clinical candidate, 55 (FXIa K = 0.7 nM), with excellent preclinical efficacy in thrombosis models and aqueous solubility suitable for intravenous administration. BMS-962212 is a reversible, direct, and highly selective small molecule inhibitor of FXIa.

PubMed: 29077405
DOI: 10.1021/acs.jmedchem.7b01171

実験手法

X-RAY DIFFRACTION (2.2 Å)