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Bioorg Med Chem Lett. 2011 May 15;21(10):2820-2. doi: 10.1016/j.bmcl.2011.03.099. Epub 2011 Apr 1.

MMP-13 selective α-sulfone hydroxamates: a survey of P1' heterocyclic amide isosteres.

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Department of Medicinal Chemistry, Pfizer Research & Development, 4901 Searle Parkway, Skokie, IL 60077, USA.


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 4.8 h half-life in rats. X-ray data (1.9 Å) for tetrazole 4c is presented.

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