1g49
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| , resolution 1.9Å | |||||||
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| Ligands: | , , | ||||||
| Gene: | MMP3 (Homo sapiens) | ||||||
| Activity: | Stromelysin 1, with EC number 3.4.24.17 | ||||||
| Related: | 1CQR, 1D5J, 1D7X, 1D8F, 1D8M, 1G05
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| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
A CARBOXYLIC ACID BASED INHIBITOR IN COMPLEX WITH MMP3
OverviewOverview
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.
DiseaseDisease
Known disease associated with this structure: Coronary heart disease, susceptibility to OMIM:[185250]
About this StructureAbout this Structure
1G49 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
Development of new hydroxamate matrix metalloproteinase inhibitors derived from functionalized 4-aminoprolines., Natchus MG, Bookland RG, De B, Almstead NG, Pikul S, Janusz MJ, Heitmeyer SA, Hookfin EB, Hsieh LC, Dowty ME, Dietsch CR, Patel VS, Garver SM, Gu F, Pokross ME, Mieling GE, Baker TR, Foltz DJ, Peng SX, Bornes DM, Strojnowski MJ, Taiwo YO, J Med Chem. 2000 Dec 28;43(26):4948-63. PMID:11150165
Page seeded by OCA on Sun Mar 30 20:36:17 2008