5QTY

FACTOR XIA IN COMPLEX WITH THE INHIBITOR ethyl (2R,7S)-7-({(2E)-3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-enoyl}amino)-15-[(methoxycarbonyl)amino]-2,3,4,5,6,7-hexahydro-1H-12,8-(metheno)-1,9-benzodiazacyclotetradecine-2-carboxylate

5QTY の概要

• エントリーDOI: 10.2210/pdb5qty/pdb
• Group deposition: FXIa (G_1002108)
• 分子名称: Coagulation factor XI, ethyl (2R,7S)-7-({(2E)-3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-enoyl}amino)-15-[(methoxycarbonyl)amino]-2,3,4,5,6,7-hexahydro-1H-12,8-(metheno)-1,9-benzodiazacyclotetradecine-2-carboxylate, SULFATE ION, ... (5 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)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 29244.46

構造登録者

Sheriff, S. (登録日: 2019-11-13, 公開日: 2020-01-29, 最終更新日: 2024-10-16)

主引用文献

Fang, T.,Corte, J.R.,Gilligan, P.J.,Jeon, Y.,Osuna, H.,Rossi, K.A.,Myers Jr., J.E.,Sheriff, S.,Lou, Z.,Zheng, J.J.,Harper, T.W.,Bozarth, J.M.,Wu, Y.,Luettgen, J.M.,Seiffert, D.A.,Wexler, R.R.,Lam, P.Y.S.
Orally bioavailable amine-linked macrocyclic inhibitors of factor XIa.
Bioorg.Med.Chem.Lett., 30:126949-126949, 2020

PubMed Abstract: The discovery of orally bioavailable FXIa inhibitors has been a challenge. Herein, we describe our efforts to address this challenge by optimization of our imidazole-based macrocyclic series. Our optimization strategy focused on modifications to the P2 prime, macrocyclic amide linker, and the imidazole scaffold. Replacing the amide of the macrocyclic linker with amide isosteres led to the discovery of substituted amine linkers which not only maintained FXIa binding affinity but also improved oral exposure in rats. Combining the optimized macrocyclic amine linker with a pyridine scaffold afforded compounds 23 and 24 that were orally bioavailable, single-digit nanomolar FXIa inhibitors with excellent selectivity against relevant blood coagulation enzymes.

PubMed: 31932224
DOI: 10.1016/j.bmcl.2020.126949

実験手法

X-RAY DIFFRACTION (1.89 Å)