Structure-Based Design and Synthesis of Potent and Selective Matrix Metalloproteinase 13 Inhibitors

We describe the use
of comparative structural analysis and structure-guided
molecular design to develop potent and selective inhibitors (10d and (S)-17b) of matrix metalloproteinase
13 (MMP-13). We applied a three-step process, starting with a comparative
analysis of the X-ray crystallographic structure of compound 5 in complex with MMP-13 with published structures of known
MMP-13·inhibitor complexes followed by molecular design and synthesis
of potent but nonselective zinc-chelating MMP inhibitors (e.g., 10a and 10b). After demonstrating that the pharmacophores
of the chelating inhibitors (S)-10a,
(R)-10a, and 10b were binding
within the MMP-13 active site, the Zn2+ chelating unit
was replaced with nonchelating polar residues that bridged over the
Zn2+ binding site and reached into a solvent accessible
area. After two rounds of structural optimization, these design approaches
led to small molecule MMP-13 inhibitors 10d and (S)-17b, which bind within the substrate-binding
site of MMP-13 and surround the catalytically active Zn2+ ion without chelating to the metal. These compounds exhibit at least
500-fold selectivity versus other MMPs.