Bioorganic & Medicinal Chemistry Letters 2011-05-15

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

Thomas E Barta, Daniel P Becker, Louis J Bedell, Alan M Easton, Susan L Hockerman, James Kiefer, Grace E Munie, Karl J Mathis, Madeleine H Li, Joseph G Rico, Clara I Villamil, Jennifer M Williams

Index: Bioorg. Med. Chem. Lett. 21(10) , 2820-2, (2011)

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Abstract

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.Copyright © 2011 Elsevier Ltd. All rights reserved.