2. Academic Validation
  3. Non-steroidal dissociated glucocorticoid agonists: indoles as A-ring mimetics and function-regulating pharmacophores

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

Affiliation

  • 1 Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, CT 06877, USA. raj.betageri@boehringer-ingelheim.com
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.

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