MMP-13 selective α-sulfone hydroxamates: A survey of P1′ heterocyclic amide isosteres

Seeking compounds preferentially potent and selective for MMP-13, we reported in the preceding Letter on a series of hydroxamic acids with a flexible benzamide tail groups.1a Here, we replace the amide moiety with non-hydrolyzable heterocycles in an effort to improve half-life. We identify a hydroxamate tetrazole 4e that spares MMP-1 and -14, shows >400-fold selectivity versus MMP-8 and >600-fold selectivity versus MMP-2, and has a 4.8h half-life in rats. X-ray data (1.9Å) for tetrazole 4c is presented.