2. Academic Validation
  3. Discovery of a potent and dissociated non-steroidal glucocorticoid receptor agonist containing an alkyl carbinol pharmacophore

Discovery of a potent and dissociated non-steroidal glucocorticoid receptor agonist containing an alkyl carbinol pharmacophore

  • Bioorg Med Chem Lett. 2014 Apr 15;24(8):1934-40. doi: 10.1016/j.bmcl.2014.03.005.
Hossein Razavi 1,  Doris Riether 2,  Christian Harcken 3,  Jörg Bentzien 2,  Roger M Dinallo 2,  Donald Souza 3,  Richard M Nelson 2,  Alison Kukulka 2,  Tazmeen N Fadra-Khan 2,  Edward J Pack Jr 2,  Ljiljana Zuvela-Jelaska 3,  Josephine Pelletier 3,  Mark Panzenbeck 3,  Carol A Torcellini 3,  John R Proudfoot 2,  Gerald H Nabozny 3,  David S Thomson 2
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877, USA. Electronic address: hossein.razavi@boehringer-ingelheim.com.
  • 2 Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877, USA.
  • 3 Department of Immunology & Inflammation, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877, USA.
PMID: 24656565 DOI: 10.1016/j.bmcl.2014.03.005
Abstract

Synthesis and structure-activity relationship (SAR) of a series of alkyl and cycloalkyl containing non-steroidal dissociated Glucocorticoid Receptor (GR) agonists is reported. This series of compounds was identified as part of an effort to replace the CF3 group in a scaffold represented by 1a. The study culminated in the identification of compound 14, a t-butyl containing derivative, which has shown potent activity for GR, selectivity against the Progesterone Receptor (PR) and the Mineralocorticoid Receptor (MR), in vitro anti-inflammatory activity in an IL-6 transrepression assay, and dissociation in a MMTV transactivation counter-screen. In a collagen-induced arthritis mouse model, 14 displayed prednisolone-like efficacy, and lower impact on body fat and free fatty acids than prednisolone at an equivalent anti-inflammatory dose.

Keywords

Agonist; Dissociated; Glucocorticoids; Non-steroidal; Nuclear hormone receptors.

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