8BO4

COAGULATION FACTOR XI PROTEASE DOMAIN IN COMPLEX WITH ACTIVE SITE INHIBITOR 1

This is a non-PDB format compatible entry.

Summary for 8BO4

• Entry DOI: 10.2210/pdb8bo4/pdb
• Descriptor: Coagulation factor XIa light chain, GLYCEROL, 4-(aminomethyl)-~{N}-[(2~{S})-1-oxidanylidene-3-phenyl-1-[[4-(1~{H}-1,2,3,4-tetrazol-5-yl)phenyl]amino]propan-2-yl]cyclohexane-1-carboxamide, ... (4 entities in total)
• Functional Keywords: s1 protease, serine protease, structure-based drug design, active site directed inhibitor, hydrolase, blood clotting
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 27396.12

Authors

Schaefer, M.,Roehrig, S.,Ackerstaff, J.,Nunez, E.J.,Gericke, K.M.,Meier, K.,Tersteegen, A.,Stampfuss, J.,Ellerbrock, P.,Meibom, M.,Lang, D.,Heitmeier, S.,Hillisch, A. (deposition date: 2022-11-14, release date: 2023-09-13, Last modification date: 2023-09-20)

Primary citation

Roehrig, S.,Ackerstaff, J.,Jimenez Nunez, E.,Teller, H.,Ellerbrock, P.,Meier, K.,Heitmeier, S.,Tersteegen, A.,Stampfuss, J.,Lang, D.,Schlemmer, K.H.,Schaefer, M.,Gericke, K.M.,Kinzel, T.,Meibom, D.,Schmidt, M.,Gerdes, C.,Follmann, M.,Hillisch, A.
Design and Preclinical Characterization Program toward Asundexian (BAY 2433334), an Oral Factor XIa Inhibitor for the Prevention and Treatment of Thromboembolic Disorders.
J.Med.Chem., 66:12203-12224, 2023

PubMed Abstract: Activated coagulation factor XI (FXIa) is a highly attractive antithrombotic target as it contributes to the development and progression of thrombosis but is thought to play only a minor role in hemostasis so that its inhibition may allow for decoupling of antithrombotic efficacy and bleeding time prolongation. Herein, we report our major efforts to identify an orally bioavailable, reversible FXIa inhibitor. Using a protein structure-based design approach, we identified a novel micromolar hit with attractive physicochemical properties. During lead modification, a critical problem was balancing potency and absorption by focusing on the most important interactions of the lead series with FXIa while simultaneously seeking to improve metabolic stability and the cytochrome P450 interaction profile. In clinical trials, the resulting compound from our extensive research program, asundexian (BAY 2433334), proved to possess the desired DMPK properties for once-daily oral dosing, and even more importantly, the initial pharmacological hypothesis was confirmed.

PubMed: 37669040
DOI: 10.1021/acs.jmedchem.3c00795

Experimental method

X-RAY DIFFRACTION (1.75 Å)