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
  • 1. Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877, USA. Electronic address: [email protected].
  • 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.