| Literature DB >> 15780611 |
Julian A Blagg1, Mark C Noe, Lilli A Wolf-Gouveia, Lawrence A Reiter, Ellen R Laird, Shang-Poa P Chang, Dennis E Danley, James T Downs, Nancy C Elliott, James D Eskra, Richard J Griffiths, Joel R Hardink, Amber I Haugeto, Christopher S Jones, Jennifer L Liras, Lori L Lopresti-Morrow, Peter G Mitchell, Jayvardhan Pandit, Ralph P Robinson, Chakrapani Subramanyam, Marcie L Vaughn-Bowser, Sue A Yocum.
Abstract
Through the use of computational modeling, a series of pyrimidinetrione-based inhibitors of MMP-13 was designed based on a lead inhibitor identified through file screening. Incorporation of a biaryl ether moiety at the C-5 position of the pyrimidinetrione ring resulted in a dramatic enhancement of MMP-13 potency. Protein crystallography revealed that this moiety binds in the S(1)(') pocket of the enzyme. Optimization of the C-4 substituent of the terminal aromatic ring led to incorporation of selectivity versus MMP-14 (MT-1 MMP). Structure activity relationships of the biaryl ether substituent are presented as is pharmacokinetic data for a compound that meets our in vitro potency and selectivity goals.Entities:
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Year: 2005 PMID： 15780611 DOI： 10.1016/j.bmcl.2005.02.038
Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823