Non-steroidal dissociated glucocorticoid agonists: indoles as A-ring mimetics and function-regulating pharmacophores

  • Bioorg Med Chem Lett. 2011 Nov 15;21(22):6842-51. doi: 10.1016/j.bmcl.2011.09.018.
Raj Betageri  1 ,  Thomas Gilmore ,  Daniel Kuzmich ,  Thomas M Kirrane ,  Jörg Bentzien ,  Dieter Wiedenmayer ,  Younes Bekkali ,  John Regan ,  Angela Berry ,  Bachir Latli ,  Alison J Kukulka ,  Tazmeen N Fadra ,  Richard M Nelson ,  Susan Goldrick ,  Ljiljana Zuvela-Jelaska ,  Don Souza ,  Josephine Pelletier ,  Roger Dinallo ,  Mark Panzenbeck ,  Carol Torcellini ,  Heewon Lee ,  Edward Pack ,  Christian Harcken ,  Gerald Nabozny ,  David S Thomson
Affiliations
  • 1. Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, CT 06877, USA. [email protected]
PMID: 21963986 DOI: 10.1016/j.bmcl.2011.09.018
Abstract

We report a SAR of non-steroidal glucocorticoid mimetics that utilize indoles as A-ring mimetics. Detailed SAR is discussed with a focus on improving PR and MR selectivity, GR agonism, and in vitro dissociation profile. SAR analysis led to compound (R)-33 which showed high PR and MR selectivity, potent agonist activity, and reduced transactivation activity in the MMTV and aromatase assays. The compound is equipotent to prednisolone in the LPS-TNF model of inflammation. In mouse CIA, at 30 mg/kg compound (R)-33 inhibited disease progression with an efficacy similar to the 3 mg/kg dose of prednisolone.