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Substituted phenyl as a steroid A-ring mimetic: Providing agonist activity to a class of arylsulfonamide nonsteroidal glucocorticoid ligands |
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| Authors: | Darren DiSalvo Daniel Kuzmich Jörg Bentzien John Regan Alison Kukulka Tazmeen Fadra-Khan Richard Nelson Christian Harcken David Thomson Gerald Nabozny |
| Institution: | 1. Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA;2. Department of Inflammation & Immunology, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA |
| Abstract: | A class of arylsulfonamide glucocorticoid receptor agonists that contains a substituted phenyl group as a steroid A-ring mimetic is reported. The structural design and SAR that provide the functional switching of a GR antagonist to an agonist is described. A combination of specific hydrogen bonding and lipophilic elements on the A-ring moiety is required to achieve potent GR agonist activity. This study culminated in the identification of compound 23 as a potent GR agonist with selectivity over the PR and MR nuclear hormone receptors. |
| Keywords: | Glucocorticoids Glucocorticoid receptor Nuclear hormone receptor Mineralocorticoid receptor Progesterone receptor Glucocorticoid receptor agonist Arylsulfonamide |
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