Nonsteroidal dissociated glucocorticoid agonists containing azaindoles as steroid A-ring mimetics.
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.
Riether
Doris
D
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
Harcken
Christian
C
Razavi
Hossein
H
Kuzmich
Daniel
D
Gilmore
Thomas
T
Bentzien
Jörg
J
Pack
Edward J
EJ
Souza
Donald
D
Nelson
Richard M
RM
Kukulka
Alison
A
Fadra
Tazmeen N
TN
Zuvela-Jelaska
Ljiljana
L
Pelletier
Josephine
J
Dinallo
Roger
R
Panzenbeck
Mark
M
Torcellini
Carol
C
Nabozny
Gerald H
GH
Thomson
David S
DS
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
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