Author/Authors :
Lawrence A. Reiter، نويسنده , , James P. Rizzi، نويسنده , , Jayvardan Pandit، نويسنده , , Michael J. Lasut، نويسنده , , Shunda M. McGahee، نويسنده , , Vinod D. Parikh، نويسنده , , James F. Blake، نويسنده , , Dennis E. Danley، نويسنده , , Ellen R. Laird، نويسنده , , Arturo Lopez-Anaya، نويسنده , , Lori L. Lopresti-Morrow، نويسنده , , Mahmoud N. Mansour، نويسنده , , Gary J. Martinelli، نويسنده , , Peter G. Mitchell، نويسنده , , Brian S. Owens، نويسنده , , Thomas A. Pauly، نويسنده , , Lisa M. Reeves، نويسنده , , Gayle K. Schulte، نويسنده , , Sue A. Yocum، نويسنده ,
Abstract :
Through the use of empirical and computational methods, phosphinate-based inhibitors of MMP-1 and MMP-13 that bind into the S2 pocket of these enzymes were designed. The synthesis and testing of 2 suggested that binding was occurring as hypothesized. Structure determination of a co-crystal of 2 bound to the catalytic domain of MMP-1 confirmed the binding mode. Substituents binding into S2, S1′, S2′ and S3′, were optimized yielding compounds with low double-digit nM IC50ʹs against these enzymes.
