title: Nonsteroidal dissociated glucocorticoid agonists containing azaindoles as steroid A-ring mimetics.
abstract: Syntheses and structure-activity relationships (SAR) of nonsteroidal glucocorticoid receptor (GR) agonists are described. These compounds contain azaindole moieties as A-ring mimetics and display various degrees of in vitro dissociation between gene transrepression and transactivation. Collagen induced arthritis studies in mouse have demonstrated that in vitro dissociated compounds (R)-16 and (R)-37 have steroid-like anti-inflammatory properties with improved metabolic side effect profiles, such as a reduced increase in body fat and serum insulin levels, compared to steroids.
authors.affiliation: Department of Medicinal Chemistry, Department of Immunology and Inflammation, and Drug Discovery Support, Boehringer-Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, Ridgefield, Connecticut 06877, USA. doris.riether@boehringer-ingelheim.com
authors.forename: Doris
authors.initials: D
authors.lastname: Riether
authors.forename: Christian
authors.initials: C
authors.lastname: Harcken
authors.forename: Hossein
authors.initials: H
authors.lastname: Razavi
authors.forename: Daniel
authors.initials: D
authors.lastname: Kuzmich
authors.forename: Thomas
authors.initials: T
authors.lastname: Gilmore
authors.forename: Jörg
authors.initials: J
authors.lastname: Bentzien
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Pack
authors.forename: Donald
authors.initials: D
authors.lastname: Souza
authors.forename: Richard M
authors.initials: RM
authors.lastname: Nelson
authors.forename: Alison
authors.initials: A
authors.lastname: Kukulka
authors.forename: Tazmeen N
authors.initials: TN
authors.lastname: Fadra
authors.forename: Ljiljana
authors.initials: L
authors.lastname: Zuvela-Jelaska
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: Gerald H
authors.initials: GH
authors.lastname: Nabozny
authors.forename: David S
authors.initials: DS
authors.lastname: Thomson
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D001141:Aromatase / Q000096:biosynthesis / Q000235:genetics; D047072:Aromatase Inhibitors / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000188:drug therapy; D001682:Biological Availability; D002478:Cells, Cultured; D004790:Enzyme Induction; D005260:Female; D006801:Humans; D006860:Hydrogen Bonding; D007328:Insulin / Q000097:blood; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D011725:Pyridines / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D011758:Pyrroles / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000819:agonists*; D013237:Stereoisomerism; D013256:Steroids / Q000737:chemistry*; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation; D000093242:Interleukin-6 Inhibitors
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001141:Aromatase; D047072:Aromatase Inhibitors; D007328:Insulin; D007375:Interleukin-1; D015850:Interleukin-6; D011725:Pyridines; D011758:Pyrroles; D011965:Receptors, Glucocorticoid; D013256:Steroids; D000093242:Interleukin-6 Inhibitors; C552710:1,1,1-trifluoro-4-(2-methoxy-5-pyrimidin-5-ylphenyl)-4-methyl-2-(1H-pyrrolo(2,3-c)pyridin-2-ylmethyl)pentan-2-ol; C552709:4-fluoro-2-(4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(1H-pyrrolo(2,3-c)pyridin-2-ylmethyl)butyl)phenol