Discovery of an in vitro and in vivo potent resorcylic lactone analog of LL-Z1640-2 as anti-inflammatory lead, II

Bioorg Med Chem Lett. 2010 May 15;20(10):3047-9. doi: 10.1016/j.bmcl.2010.03.119. Epub 2010 Apr 9.

Abstract

The potent in vitro lead compound, ER-803064 (2), a MEK1 and MEKK1 inhibitor inspired from natural product LL-Z1640-2 (f152A1), was further optimized to improve in vitro and in vivo potency. The modifications on C14 position led to discovery of the lead compounds 28 and 29, which regained full in vitro potency of f152A1 and showed higher in vivo potency by iv administration.

MeSH terms

  • Anti-Inflammatory Agents / chemical synthesis
  • Anti-Inflammatory Agents / chemistry*
  • Anti-Inflammatory Agents / pharmacology
  • Drug Discovery
  • Lactones / chemical synthesis
  • Lactones / chemistry*
  • Lactones / pharmacology
  • MAP Kinase Kinase 1 / antagonists & inhibitors
  • MAP Kinase Kinase 1 / metabolism
  • Structure-Activity Relationship

Substances

  • Anti-Inflammatory Agents
  • LL Z1640-2
  • Lactones
  • MAP Kinase Kinase 1