Non-steroidal dissociated glucocorticoid agonists: indoles as A-ring mimetics and function-regulating pharmacophores |
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Authors: | Betageri Raj Gilmore Thomas Kuzmich Daniel Kirrane Thomas M Bentzien Jörg Wiedenmayer Dieter Bekkali Younes Regan John Berry Angela Latli Bachir Kukulka Alison J Fadra Tazmeen N Nelson Richard M Goldrick Susan Zuvela-Jelaska Ljiljana Souza Don Pelletier Josephine Dinallo Roger Panzenbeck Mark Torcellini Carol Lee Heewon Pack Edward Harcken Christian Nabozny Gerald Thomson David S |
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Affiliation: | Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, CT 06877, USA. raj.betageri@boehringer-ingelheim.com |
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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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Keywords: | Non-steroidal glucocorticoid agonist Dissociated activity Function-regulating pharmacophore |
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