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

Summary for 5QCM

• Entry DOI: 10.2210/pdb5qcm/pdb
• Group deposition: FXIa (G_1002041)
• Related: 5QCK 5QCL 5QCN
• Descriptor: 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)
• Functional Keywords: hydrolase, serine protease, blood coagulation factor, protein inhibitor complex, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Secreted: P03951
• Total number of polymer chains: 1
• Total formula weight: 29203.40

Authors

Sheriff, S. (deposition date: 2017-08-10, release date: 2017-11-08, Last modification date: 2024-11-20)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.2 Å)