Discovery of a potent, metabolically stabilized resorcylic lactone as an anti-inflammatory lead

  • Bioorg Med Chem Lett. 2009 Nov 1;19(21):6196-9. doi: 10.1016/j.bmcl.2009.08.096.
H Du  1 ,  T Matsushima ,  M Spyvee ,  M Goto ,  H Shirota ,  F Gusovsky ,  K Chiba ,  M Kotake ,  N Yoneda ,  Y Eguchi ,  L DiPietro ,  J-C Harmange ,  S Gilbert ,  X-Y Li ,  H Davis ,  Y Jiang ,  Z Zhang ,  R Pelletier ,  N Wong ,  H Sakurai ,  H Yang ,  H Ito-Igarashi ,  A Kimura ,  Y Kuboi ,  Y Mizui ,  I Tanaka ,  M Ikemori-Kawada ,  Y Kawakami ,  A Inoue ,  T Kawai ,  Y Kishi ,  Y Wang
Affiliations
  • 1. Eisai Research Institute of Boston, 4 Corporate Drive, Andover, MA 01810, USA.
PMID: 19783437 DOI: 10.1016/j.bmcl.2009.08.096
Abstract

With bioactivity-guided phenotype screenings, a potent anti-inflammatory compound f152A1 has been isolated, characterized and identified as the known natural product LL-Z1640-2. Metabolic instability precluded its use for the study on animal disease models. Via total synthesis, a potent, metabolically stabilized analog ER-803064 has been created; addition of the (S)-Me group at C4 onto f152A1 has resulted in a dramatic improvement on its metabolic stability, while preserving the anti-inflammatory activities.