title: Non-steroidal dissociated glucocorticoid agonists: indoles as A-ring mimetics and function-regulating pharmacophores.
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.
authors.affiliation: Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, CT 06877, USA. raj.betageri@boehringer-ingelheim.com
authors.forename: Raj
authors.initials: R
authors.lastname: Betageri
authors.forename: Thomas
authors.initials: T
authors.lastname: Gilmore
authors.forename: Daniel
authors.initials: D
authors.lastname: Kuzmich
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Kirrane
authors.forename: Jörg
authors.initials: J
authors.lastname: Bentzien
authors.forename: Dieter
authors.initials: D
authors.lastname: Wiedenmayer
authors.forename: Younes
authors.initials: Y
authors.lastname: Bekkali
authors.forename: John
authors.initials: J
authors.lastname: Regan
authors.forename: Angela
authors.initials: A
authors.lastname: Berry
authors.forename: Bachir
authors.initials: B
authors.lastname: Latli
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Kukulka
authors.forename: Tazmeen N
authors.initials: TN
authors.lastname: Fadra
authors.forename: Richard M
authors.initials: RM
authors.lastname: Nelson
authors.forename: Susan
authors.initials: S
authors.lastname: Goldrick
authors.forename: Ljiljana
authors.initials: L
authors.lastname: Zuvela-Jelaska
authors.forename: Don
authors.initials: D
authors.lastname: Souza
authors.forename: Josephine
authors.initials: J
authors.lastname: Pelletier
authors.forename: Roger
authors.initials: R
authors.lastname: Dinallo
authors.forename: Mark
authors.initials: M
authors.lastname: Panzenbeck
authors.forename: Carol
authors.initials: C
authors.lastname: Torcellini
authors.forename: Heewon
authors.initials: H
authors.lastname: Lee
authors.forename: Edward
authors.initials: E
authors.lastname: Pack
authors.forename: Christian
authors.initials: C
authors.lastname: Harcken
authors.forename: Gerald
authors.initials: G
authors.lastname: Nabozny
authors.forename: David S
authors.initials: DS
authors.lastname: Thomson
mesh_terms: D000818:Animals; D005938:Glucocorticoids / Q000737:chemistry* / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology*; D051379:Mice; D008958:Models, Molecular; D011965:Receptors, Glucocorticoid / Q000819:agonists* / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D005938:Glucocorticoids; D007211:Indoles; D011965:Receptors, Glucocorticoid