1G49

A CARBOXYLIC ACID BASED INHIBITOR IN COMPLEX WITH MMP3

Summary for 1G49

• Entry DOI: 10.2210/pdb1g49/pdb
• Related: 1CQR 1D5J 1D7X 1D8F 1D8M 1G05
• Descriptor: MATRIX METALLOPROTEINASE 3, ZINC ION, CALCIUM ION, ... (5 entities in total)
• Functional Keywords: mixed alpha beta structure, zinc protease, inhibited, hydrolase
• Biological source: Homo sapiens (human)
• Cellular location: Secreted, extracellular space, extracellular matrix : P08254
• Total number of polymer chains: 2
• Total formula weight: 39770.68

Authors

Natchus, M.G.,Bookland, R.G.,De, B.,Almstead, N.G.,Pikul, S. (deposition date: 2000-10-26, release date: 2001-10-24, Last modification date: 2024-02-07)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.9 Å)