8BO7

COAGULATION FACTOR XI PROTEASE DOMAIN IN COMPLEX WITH ACTIVE SITE INHIBITOR 34

これはPDB形式変換不可エントリーです。

8BO7 の概要

• エントリーDOI: 10.2210/pdb8bo7/pdb
• 分子名称: Coagulation factor XIa light chain, 4-[[(2~{S})-2-[4-(5-chloranyl-2-cyano-phenyl)-3-methoxy-6-oxidanylidene-2,5-dihydropyridin-1-yl]-3-[(2~{S})-oxan-2-yl]propanoyl]amino]benzoic acid, CITRIC ACID, ... (5 entities in total)
• 機能のキーワード: s1 protease, serine protease, structure-based drug design, active site directed inhibitor, hydrolase, blood clotting
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 27708.75

構造登録者

Schaefer, M.,Roehrig, S.,Ackerstaff, J.,Nunez, E.J.,Gericke, K.M.,Meier, K.,Tersteegen, A.,Stampfuss, J.,Ellerbrock, P.,Meibom, D.,Lang, D.,Heitmeier, S.,Hillisch, A. (登録日: 2022-11-14, 公開日: 2023-09-13, 最終更新日: 2024-10-23)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.25 Å)