7V16

Factor XIa in Complex with Compound 2j

7V16 の概要

• エントリーDOI: 10.2210/pdb7v16/pdb
• 分子名称: Coagulation factor XIa light chain, CITRIC ACID, 5-[3-chloranyl-2-fluoranyl-6-(1,2,3,4-tetrazol-1-yl)phenyl]-2-[(1~{R})-2-cyclopropyl-1-[4-(2-methylpyrazol-3-yl)pyrazol-1-yl]ethyl]-1-oxidanyl-pyridine, ... (4 entities in total)
• 機能のキーワード: hydrolase, serine protease, coagulation factor, 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: 27554.56

構造登録者

Shaffer, P.L.,Milligan, C.M. (登録日: 2022-05-11, 公開日: 2022-08-03, 最終更新日: 2023-10-18)

主引用文献

Xu, G.,Liu, Z.,Wang, X.,Lu, T.,DesJarlais, R.L.,Thieu, T.,Zhang, J.,Devine, Z.H.,Du, F.,Li, Q.,Milligan, C.M.,Shaffer, P.,Cedervall, P.E.,Spurlino, J.C.,Stratton, C.F.,Pietrak, B.,Szewczuk, L.M.,Wong, V.,Steele, R.A.,Bruinzeel, W.,Chintala, M.,Silva, J.,Gaul, M.D.,Macielag, M.J.,Nargund, R.
Discovery of Potent and Orally Bioavailable Pyridine N-Oxide-Based Factor XIa Inhibitors through Exploiting Nonclassical Interactions.
J.Med.Chem., 65:10419-10440, 2022

PubMed Abstract: Activated factor XI (FXIa) inhibitors are promising novel anticoagulants with low bleeding risk compared with current anticoagulants. The discovery of potent FXIa inhibitors with good oral bioavailability has been challenging. Herein, we describe our discovery effort, utilizing nonclassical interactions to improve potency, cellular permeability, and oral bioavailability by enhancing the binding while reducing polar atoms. Beginning with literature-inspired pyridine N-oxide-based FXIa inhibitor , the imidazole linker was first replaced with a pyrazole moiety to establish a polar C-H···water hydrogen-bonding interaction. Then, structure-based drug design was employed to modify lead molecule in the P1' and P2' regions, with substituents interacting with key residues through various nonclassical interactions. As a result, a potent FXIa inhibitor ( = 0.17 nM) was discovered. This compound demonstrated oral bioavailability in preclinical species (rat 36.4%, dog 80.5%, and monkey 43.0%) and displayed a dose-dependent antithrombotic effect in a rabbit arteriovenous shunt model of thrombosis.

PubMed: 35862732
DOI: 10.1021/acs.jmedchem.2c00442

実験手法

X-RAY DIFFRACTION (1.505 Å)