Betageri Raj, Zhang Yan, Zindell Renee M, Kuzmich Daniel, Kirrane Thomas M, Bentzien Jörg, Cardozo Mario, Capolino Alison J, Fadra Tazmeen N, Nelson Richard M, Paw Zofia, Shih Daw-Tsun, Shih Cheng-Kon, Zuvela-Jelaska Ljiljana, Nabozny Gerald, Thomson David S
Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, P.O. Box 368, Ridgefield, CT 06877, USA.
Bioorg Med Chem Lett. 2005 Nov 1;15(21):4761-9. doi: 10.1016/j.bmcl.2005.07.025.
Compound 1, a potent glucocorticoid receptor ligand, contains a quaternary carbon bearing trifluoromethyl and hydroxyl groups. This paper describes the effect of replacing the trifluoromethyl group on binding and agonist activity of the GR ligand 1. The results illustrate that replacing the CF3 group with a cyclohexylmethyl or benzyl group maintains the GR binding potency. These substitutions alter the functional behavior of the GR ligands from agonists to antagonists. Docking studies suggest that the benzyl analog 19 binds in a similar fashion as the GR antagonist, RU486. The central benzyl group of 19 and the C-11 dimethylaniline moiety of RU486 overlay. Binding of compound 19 is believed to force helix 12 to adopt an open conformation and this leads to the antagonist properties of the non-CF3 ligands carrying a large group at the center of the molecule.
