Discovery of betamethasone 17alpha-carbamates as dissociated glucocorticoid receptor modulators in the rat.
A series of betamethasone 17alpha-carbamates were designed, synthesized, and evaluated for their ability to dissociate the two main functions of the glucocorticoid receptor, that is, transactivation and transrepression, in rat cell lines. A number of alkyl substituted betamethasone 17alpha-carbamates were identified with excellent affinity for the glucocorticoid receptor (e.g., 7, GR IC(50) 5.1 nM) and indicated dissociated profiles in functional assays of transactivation (rat tyrosine aminotransferase, TAT, and rat glutamine synthetase, GS) and transrepression (human A549 cells, MMP-1 assay). Gratifyingly, the in-vivo profile of these compounds, for example, 7, also indicated potent anti-inflammatory activity with impaired effects on glucose, insulin, triglycerides, and body weight. Taken together, these results indicate that dissociated glucocorticoid receptor modulators can be identified in rodents.
Ali
Amjad
A
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, United States. amjad_ali@merck.com
Balkovec
James M
JM
Greenlee
Mark
M
Hammond
Milton L
ML
Rouen
Greg
G
Taylor
Gayle
G
Einstein
Monica
M
Ge
Lan
L
Harris
Georgianna
G
Kelly
Terri M
TM
Mazur
Paul
P
Pandit
Shilpa
S
Santoro
Joseph
J
Sitlani
Ayesha
A
Wang
Chuanlin
C
Williamson
Joann
J
Forrest
Michael J
MJ
Carballo-Jane
Ester
E
Luell
Silvi
S
Lowitz
Karen
K
Visco
Denise
D
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001623:Betamethasone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism; D007328:Insulin / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000737:chemistry / Q000378:metabolism*; D014280:Triglycerides / Q000097:blood; D014444:Tyrosine Transaminase / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D001786:Blood Glucose; D002219:Carbamates; D007328:Insulin; D011965:Receptors, Glucocorticoid; D014280:Triglycerides; D001623:Betamethasone; D014444:Tyrosine Transaminase; D020781:Matrix Metalloproteinase 1; D005974:Glutamate-Ammonia Ligase