8TWX

Synthesis and Evaluation of Diaryl Ether Modulators of the Leukotriene A4 Hydrolase Aminopeptidase Activity

8TWX の概要

• エントリーDOI: 10.2210/pdb8twx/pdb
• 分子名称: Leukotriene A-4 hydrolase, 5-[4-(4-chlorophenoxy)phenyl]-1H-pyrazol-3-amine, ZINC ION, ... (4 entities in total)
• 機能のキーワード: leukotriene a4 hydrolase, 4mdm, aminipeptidase, activator, hydrolase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 207447.86

構造登録者

Lee, K.H.,Lee, S.H.,Paige, M.,Noble, S.M. (登録日: 2023-08-21, 公開日: 2024-08-28, 最終更新日: 2025-03-05)

主引用文献

Petruncio, G.,Lee, K.H.,Girgis, M.,Shellnutt, Z.,Beaulac, Z.,Xiang, J.,Lee, S.H.,Peng, X.,Burdick, M.,Noble, S.M.,Shim, Y.M.,Paige, M.
Synthesis and Evaluation of diaryl ether modulators of the leukotriene A 4 hydrolase aminopeptidase activity.
Eur.J.Med.Chem., 272:116459-116459, 2024

PubMed Abstract: Activation of the aminopeptidase (AP) activity of leukotriene A hydrolase (LTAH) presents a potential therapeutic strategy for resolving chronic inflammation. Previously, ARM1 and derivatives were found to activate the AP activity using the alanine-p-nitroanilide (Ala-pNA) as a reporter group in an enzyme kinetics assay. As an extension of this previous work, novel ARM1 derivatives were synthesized using a palladium-catalyzed Ullmann coupling reaction and screened using the same assay. Analogue 5, an aminopyrazole (AMP) analogue of ARM1, was found to be a potent AP activator with an AC of 0.12 μM. An X-ray crystal structure of LTAH in complex with AMP was refined at 2.7 Å. Despite its AP activity with Ala-pNA substrate, AMP did not affect hydrolysis of the previously proposed natural ligand of LTAH, Pro-Gly-Pro (PGP). This result highlights a discrepancy between the hydrolysis of more conveniently monitored chromogenic synthetic peptides typically employed in assays and endogenous peptides. The epoxide hydrolase (EH) activity of AMP was measured in vivo and the compound significantly reduced leukotriene B (LTB) levels in a murine bacterial pneumonia model. However, AMP did not enhance survival in the murine pneumonia model over a 14-day period. A liver microsome stability assay showed metabolic stability of AMP. The results suggested that accelerated Ala-pNA cleavage is not sufficient for predicting therapeutic potential, even when the full mechanism of activation is known.

PubMed: 38704942
DOI: 10.1016/j.ejmech.2024.116459

実験手法

X-RAY DIFFRACTION (2.7 Å)