5QTU

FACTOR XIA IN COMPLEX WITH THE INHIBITOR methyl [(3R,7S)-7-{[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-imidazole-4-carbonyl]amino}-3-methyl-2-oxo-2,3,4,5,6,7-hexahydro-1H-12,8-(metheno)-1,9-benzodiazacyclotetradecin-15-yl]carbamate

5QTU の概要

• エントリーDOI: 10.2210/pdb5qtu/pdb
• Group deposition: FXIa (G_1002107)
• 分子名称: Coagulation factor XI, methyl [(3R,7S)-7-{[1-(3-chloro-2-fluorophenyl)-5-methyl-1H-imidazole-4-carbonyl]amino}-3-methyl-2-oxo-2,3,4,5,6,7-hexahydro-1H-12,8-(metheno)-1,9-benzodiazacyclotetradecin-15-yl]carbamate, SULFATE ION, ... (6 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); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 31019.49

構造登録者

Sheriff, S. (登録日: 2019-10-16, 公開日: 2019-12-25, 最終更新日: 2026-02-18)

主引用文献

Corte, J.R.,Pinto, D.J.P.,Fang, T.,Osuna, H.,Yang, W.,Wang, Y.,Lai, A.,Clark, C.,Sun, J.H.,Rampulla, R.A.,Mathur, A.,Kaspady, M.,Neithnadka, P.R.,Li, Y.X.,Rossi, K.A.,Myers, J.E.,Sheriff, S.,Lou, Z.,Harper, T.W.,Huang, C.S.,Zheng, J.J.,Bozarth, J.M.,Wu, Y.,Wong, P.C.,Crain, E.,Seiffert, D.A.,Luettgen, J.M.,Lam, P.,Wexler, R.R.,Ewing, W.R.
Potent, Orally Bioavailable and Efficacious Macrocyclic Inhibitors of Factor XIa. Discovery of Pyridine-Based Macrocycles Possessing Phenylazole Carboxamide P1 Groups.
J.Med.Chem., 63:784-803, 2019

PubMed Abstract: Factor XIa (FXIa) inhibitors are promising novel anticoagulants, which show excellent efficacy in preclinical thrombosis models with minimal effects on hemostasis. The discovery of potent and selective FXIa inhibitors which are also orally bioavailable has been a challenge. Here, we describe optimization of the imidazole-based macrocyclic series and our initial progress toward meeting this challenge. A two-pronged strategy, which focused on replacement of the imidazole scaffold and the design of new P1 groups, led to the discovery of potent, orally bioavailable pyridine-based macrocyclic FXIa inhibitors. Moreover, pyridine-based macrocycle , possessing the phenylimidazole carboxamide P1, exhibited excellent selectivity against relevant blood coagulation enzymes and displayed antithrombotic efficacy in a rabbit thrombosis model.

PubMed: 31833761
DOI: 10.1021/acs.jmedchem.9b01768

実験手法

X-RAY DIFFRACTION (2.53 Å)