1g49: Difference between revisions

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{{STRUCTURE_1g49|  PDB=1g49  |  SCENE=  }}  
{{STRUCTURE_1g49|  PDB=1g49  |  SCENE=  }}  


'''A CARBOXYLIC ACID BASED INHIBITOR IN COMPLEX WITH MMP3'''
===A CARBOXYLIC ACID BASED INHIBITOR IN COMPLEX WITH MMP3===




==Overview==
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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.
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{{ABSTRACT_PUBMED_11150165}}


==Disease==
==Disease==
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[[Category: Mixed alpha beta structure]]
[[Category: Mixed alpha beta structure]]
[[Category: Zinc protease]]
[[Category: Zinc protease]]
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Revision as of 04:23, 1 July 2008

File:1g49.png

Template:STRUCTURE 1g49

A CARBOXYLIC ACID BASED INHIBITOR IN COMPLEX WITH MMP3A CARBOXYLIC ACID BASED INHIBITOR IN COMPLEX WITH MMP3

Template:ABSTRACT PUBMED 11150165

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

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