title: Novel ketal ligands for the glucocorticoid receptor: in vitro and in vivo activity.
abstract: A novel series of selective ligands for the human glucocorticoid receptor is described. Structure-activity studies focused on variation of B-ring size, ketal ring size, and ketal substitution. These analogs were found to be potent and selective ligands for GR and have partial agonist profiles in functional assays for transactivation (TAT, GS) and transrepression (IL-6). Of these compounds, 27, 28, and 35 were evaluated further in a mouse LPS-induced TNF-alpha secretion model. Compound 28 had an ED(50) of 14.1 mg/kg compared with 0.5 mg/kg for prednisolone in the same assay.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. cameron_smith@merck.com
authors.forename: Cameron J
authors.initials: CJ
authors.lastname: Smith
authors.forename: Amjad
authors.initials: A
authors.lastname: Ali
authors.forename: James M
authors.initials: JM
authors.lastname: Balkovec
authors.forename: Donald W
authors.initials: DW
authors.lastname: Graham
authors.forename: Milton L
authors.initials: ML
authors.lastname: Hammond
authors.forename: Gool F
authors.initials: GF
authors.lastname: Patel
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Rouen
authors.forename: Scott K
authors.initials: SK
authors.lastname: Smith
authors.forename: James R
authors.initials: JR
authors.lastname: Tata
authors.forename: Monica
authors.initials: M
authors.lastname: Einstein
authors.forename: Lan
authors.initials: L
authors.lastname: Ge
authors.forename: Georgianna S
authors.initials: GS
authors.lastname: Harris
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Kelly
authors.forename: Paul
authors.initials: P
authors.lastname: Mazur
authors.forename: Chris M
authors.initials: CM
authors.lastname: Thompson
authors.forename: Chuanlin F
authors.initials: CF
authors.lastname: Wang
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Williamson
authors.forename: Douglas K
authors.initials: DK
authors.lastname: Miller
authors.forename: Shilpa
authors.initials: S
authors.lastname: Pandit
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Santoro
authors.forename: Ayesha
authors.initials: A
authors.lastname: Sitlani
authors.forename: Ting-Ting D
authors.initials: TT
authors.lastname: Yamin
authors.forename: Edward A
authors.initials: EA
authors.lastname: O'Neill
authors.forename: Dennis M
authors.initials: DM
authors.lastname: Zaller
authors.forename: Ester
authors.initials: E
authors.lastname: Carballo-Jane
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Forrest
authors.forename: Silvi
authors.initials: S
authors.lastname: Luell
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D051379:Mice; D011965:Receptors, Glucocorticoid / Q000378:metabolism*
chemical_list: D008024:Ligands; D011965:Receptors, Glucocorticoid