The design and synthesis of novel N-hydroxyformamide inhibitors of ADAM-TS4 for the treatment of osteoarthritis

  • Bioorg Med Chem Lett. 2011 Mar 1;21(5):1376-81. doi: 10.1016/j.bmcl.2011.01.036.
Chris De Savi  1 ,  Andrew Pape ,  John G Cumming ,  Attilla Ting ,  Peter D Smith ,  Jeremy N Burrows ,  Mark Mills ,  Chris Davies ,  Scott Lamont ,  David Milne ,  Calum Cook ,  Peter Moore ,  Yvonne Sawyer ,  Stefan Gerhardt
Affiliations
  • 1. Respiratory and Inflammation Research Area, AstraZeneca, Alderley Park, Macclesfield, Cheshire, UK. [email protected]
PMID: 21300546 DOI: 10.1016/j.bmcl.2011.01.036
Abstract

Two series of N-hydroxyformamide inhibitors of ADAM-TS4 were identified from screening compounds previously synthesised as inhibitors of matrix metalloproteinase-13 (collagenase-3). Understanding of the binding mode of this class of compound using ADAM-TS1 as a structural surrogate has led to the discovery of potent and very selective inhibitors with favourable DMPK properties. Synthesis, structure-activity relationships, and strategies to improve selectivity and lower in vivo metabolic clearance are described.

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