Author/Authors :
Julian A. Blagg، نويسنده , , Mark C. Noe، نويسنده , , Lilli A. Wolf-Gouveia، نويسنده , , Lawrence A. Reiter، نويسنده , , Ellen R. Laird، نويسنده , , Shang-Poa P. Chang، نويسنده , , Dennis E. Danley، نويسنده , , James T. Downs، نويسنده , , Nancy C. Elliott، نويسنده , , James D. Eskra، نويسنده , , Richard J. Griffiths، نويسنده , , Joel R. Hardink، نويسنده , , Amber I. Haugeto، نويسنده , , Christopher S. Jones، نويسنده , , Jennifer L. Liras، نويسنده , , Lori L. Lopresti-Morrow، نويسنده , , Peter G. Mitchell، نويسنده , , Jayvardhan Pandit، نويسنده , , Ralph P. Robinson، نويسنده , , Chakrapani Subramanyam، نويسنده , , et al، نويسنده ,
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 S1′ 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.
