4YES

Thrombin in complex with (S)-(4-chloro-2-((1-(5-methyl-1H-pyrrole-2-carbonyl)pyrrolidine-2-carboxamido)methyl)phenyl)methanaminium

4YES の概要

• エントリーDOI: 10.2210/pdb4yes/pdb
• 関連するBIRD辞書のPRD_ID: PRD_002146
• 分子名称: Thrombin light chain, Thrombin heavy chain, Hirudin, ... (8 entities in total)
• 機能のキーワード: sulfo-hirudin, inhibitor, complex, thrombin, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (Human); 詳細
• 細胞内の位置: Secreted, extracellular space: P00734 P00734; Secreted: P01050
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 36163.84

構造登録者

Orth, P. (登録日: 2015-02-24, 公開日: 2015-06-17, 最終更新日: 2024-11-06)

主引用文献

Chobanian, H.R.,Pio, B.,Guo, Y.,Shen, H.,Huffman, M.A.,Madeira, M.,Salituro, G.,Terebetski, J.L.,Ormes, J.,Jochnowitz, N.,Hoos, L.,Zhou, Y.,Lewis, D.,Hawes, B.,Mitnaul, L.,O'Neill, K.,Ellsworth, K.,Wang, L.,Biftu, T.,Duffy, J.L.
Improved Stability of Proline-Derived Direct Thrombin Inhibitors through Hydroxyl to Heterocycle Replacement.
Acs Med.Chem.Lett., 6:553-557, 2015

PubMed Abstract: Modification of the previously disclosed (S)-N-(2-(aminomethyl)-5-chlorobenzyl)-1-((R)-2-hydroxy-3,3-dimethylbutanoyl)pyrrolidine-2-carboxamide 2 by optimization of the P3 group afforded novel, low molecular weight thrombin inhibitors. Heterocycle replacement of the hydroxyl functional group helped maintain thrombin in vitro potency while improving the chemical stability and pharmacokinetic profile. These modifications led to the identification of compound 10, which showed excellent selectivity over related serine proteases as well as in vivo efficacy in the rat arteriovenous shunt. Compound 10 exhibited significantly improved chemical stability and pharmacokinetic properties over 2 and may be utilized as a structurally differentiated preclinical tool comparator to dabigatran etexilate (Pro-1) to interrogate the on- and off-target effects of oral direct thrombin inhibitors.

PubMed: 26005532
DOI: 10.1021/acsmedchemlett.5b00047

実験手法

X-RAY DIFFRACTION (1.5 Å)