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Non-steroidal dissociated glucocorticoid agonists: indoles as A-ring mimetics and function-regulating pharmacophores
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
Affiliation:Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, CT 06877, USA. raj.betageri@boehringer-ingelheim.com
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.
Keywords:Non-steroidal glucocorticoid agonist   Dissociated activity   Function-regulating pharmacophore
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