A novel series of highly selective inhibitors of MMP-3

The design and synthesis of a series of highly selective hydroxamate inhibitors of stromelysin-1 (MMP-3) is described. Substitution of a 4-biaryl piperidine sulfonamide core, which binds at the S1′ subsite of MMP-3, was optimised to give potent inhibitors of MMP-3, with greater than 300-fold selectivity over MMP-1, MMP-2, MMP-9 and MMP-14. Compounds 26 and 27 were identified as having the best balance of pharmacology and properties required for topical drug delivery.

Graphical abstractThe design and synthesis of a series of highly selective hydroxamate inhibitors of MMP-3 is described. Substitution of a 4-biaryl piperidine sulfonamide core was optimised to give potent inhibitors of MMP-3, with greater than 300-fold selectivity over MMP-1, MMP-2, MMP-9 and MMP-14.Figure optionsDownload full-size imageDownload as PowerPoint slide