7MBO

FACTOR XIA (PICHIA PASTORIS; C500S [C122S]) IN COMPLEX WITH THE INHIBITOR Milvexian (BMS-986177), IUPAC NAME:(6R,10S)-10-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6- oxopyrimidin-1(6H)-yl}-1-(difluoromethyl)-6-methyl-1,4,7,8,9,10-hexahydro-15,11- (metheno)pyrazolo[4,3-b][1,7]diazacyclotetradecin-5(6H)-one

Summary for 7MBO

• Entry DOI: 10.2210/pdb7mbo/pdb
• Descriptor: Coagulation factor XIa light chain, 2-acetamido-2-deoxy-beta-D-glucopyranose, Milvexian, ... (4 entities in total)
• Functional Keywords: hydrolase, serine protease, coagulation factor, syntethic inhibitor, blood, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 27704.15

Authors

Sheriff, S. (deposition date: 2021-04-01, release date: 2021-09-15, Last modification date: 2023-10-18)

Primary citation

Dilger, A.K.,Pabbisetty, K.B.,Corte, J.R.,De Lucca, I.,Fang, T.,Yang, W.,Pinto, D.J.P.,Wang, Y.,Zhu, Y.,Mathur, A.,Li, J.,Hou, X.,Smith, D.,Sun, D.,Zhang, H.,Krishnananthan, S.,Wu, D.R.,Myers Jr., J.E.,Sheriff, S.,Rossi, K.A.,Chacko, S.,Zheng, J.J.,Galella, M.A.,Ziemba, T.,Dierks, E.A.,Bozarth, J.M.,Wu, Y.,Crain, E.,Wong, P.C.,Luettgen, J.M.,Wexler, R.R.,Ewing, W.R.
Discovery of Milvexian, a High-Affinity, Orally Bioavailable Inhibitor of Factor XIa in Clinical Studies for Antithrombotic Therapy.
J.Med.Chem., 65:1770-1785, 2022

PubMed Abstract: Factor XIa (FXIa) is an enzyme in the coagulation cascade thought to amplify thrombin generation but has a limited role in hemostasis. From preclinical models and human genetics, an inhibitor of FXIa has the potential to be an antithrombotic agent with superior efficacy and safety. Reversible and irreversible inhibitors of FXIa have demonstrated excellent antithrombotic efficacy without increased bleeding time in animal models (Weitz, J. I., Chan, N. C. 2019, 39 (1), 7-12). Herein, we report the discovery of a novel series of macrocyclic FXIa inhibitors containing a pyrazole P2' moiety. Optimization of the series for (pharmacokinetic) PK properties, free fraction, and solubility resulted in the identification of (, , FXIa = 0.11 nM) as a clinical candidate for the prevention and treatment of thromboembolic disorders, suitable for oral administration.

PubMed: 34494428
DOI: 10.1021/acs.jmedchem.1c00613

Experimental method

X-RAY DIFFRACTION (0.924 Å)