1G49

A CARBOXYLIC ACID BASED INHIBITOR IN COMPLEX WITH MMP3

1G49 の概要

• エントリーDOI: 10.2210/pdb1g49/pdb
• 関連するPDBエントリー: 1CQR 1D5J 1D7X 1D8F 1D8M 1G05
• 分子名称: MATRIX METALLOPROTEINASE 3, ZINC ION, CALCIUM ION, ... (5 entities in total)
• 機能のキーワード: mixed alpha beta structure, zinc protease, inhibited, hydrolase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Secreted, extracellular space, extracellular matrix : P08254
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 39770.68

構造登録者

Natchus, M.G.,Bookland, R.G.,De, B.,Almstead, N.G.,Pikul, S. (登録日: 2000-10-26, 公開日: 2001-10-24, 最終更新日: 2024-02-07)

主引用文献

Natchus, M.G.,Bookland, R.G.,De, B.,Almstead, N.G.,Pikul, S.
Development of new hydroxamate matrix metalloproteinase inhibitors derived from functionalized 4-aminoprolines.
J.Med.Chem., 43:4948-4963, 2000

PubMed Abstract: A series of hydroxamates was prepared from an aminoproline scaffold and tested for efficacy as matrix metalloproteinase (MMP) inhibitors. Detailed SAR for the series is reported for five enzymes within the MMP family, and a number of inhibitors, such as compound 47, display broad-spectrum activity with sub-nanomolar potency for some enzymes. Modifications of the P1' portion of the molecule played a key role in affecting both potency and selectivity within the MMP family. Longer-chain aliphatic substituents in this region of the molecule tended to increase potency for MMP-3 and decrease potency for MMP-1, as exemplified by compounds 48-50, while aromatic substituents, as in compound 52, generated broad-spectrum inhibition. The data is rationalized based upon X-ray crystal data which is also presented. While the in vitro peroral absorption seemed to be less predictable, it tended to decrease with longer and more hydrophilic substituents. Finally, a rat model of osteoarthritis was used to evaluate the efficacy of these compounds, and a direct link was established between their pharmacokinetics and their in vivo efficacy.

PubMed: 11150165
DOI: 10.1021/jm000246e

実験手法

X-RAY DIFFRACTION (1.9 Å)