title: Discovery of betamethasone 17alpha-carbamates as dissociated glucocorticoid receptor modulators in the rat.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, United States. amjad_ali@merck.com
authors.forename: Amjad
authors.initials: A
authors.lastname: Ali
authors.forename: James M
authors.initials: JM
authors.lastname: Balkovec
authors.forename: Mark
authors.initials: M
authors.lastname: Greenlee
authors.forename: Milton L
authors.initials: ML
authors.lastname: Hammond
authors.forename: Greg
authors.initials: G
authors.lastname: Rouen
authors.forename: Gayle
authors.initials: G
authors.lastname: Taylor
authors.forename: Monica
authors.initials: M
authors.lastname: Einstein
authors.forename: Lan
authors.initials: L
authors.lastname: Ge
authors.forename: Georgianna
authors.initials: G
authors.lastname: Harris
authors.forename: Terri M
authors.initials: TM
authors.lastname: Kelly
authors.forename: Paul
authors.initials: P
authors.lastname: Mazur
authors.forename: Shilpa
authors.initials: S
authors.lastname: Pandit
authors.forename: Joseph
authors.initials: J
authors.lastname: Santoro
authors.forename: Ayesha
authors.initials: A
authors.lastname: Sitlani
authors.forename: Chuanlin
authors.initials: C
authors.lastname: Wang
authors.forename: Joann
authors.initials: J
authors.lastname: Williamson
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Forrest
authors.forename: Ester
authors.initials: E
authors.lastname: Carballo-Jane
authors.forename: Silvi
authors.initials: S
authors.lastname: Luell
authors.forename: Karen
authors.initials: K
authors.lastname: Lowitz
authors.forename: Denise
authors.initials: D
authors.lastname: Visco
mesh_terms: 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
chemical_list: 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