title: Novel glucocorticoids containing a 6,5-bicyclic core fused to a pyrazole ring: synthesis, in vitro profile, molecular modeling studies, and in vivo experiments.
abstract: Chemistry was developed to synthesize the title series of compounds. The ability of these novel ligands to bind to the glucocorticoid receptor was investigated. These compounds were also tested in a series of functional assays and some were found to display the profile of a dissociated glucocorticoid. The SAR of the 6,5-bicyclic series differed markedly from the previously reported 6,6-series. Molecular modeling studies were employed to understand the conformational differences between the two series of compounds, which may explain their divergent activity. Two compounds were profiled in vivo and shown to reduce inflammation in a mouse model. An active metabolite is suspected in one case.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA. christopher_thompson@merck.com
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Thompson
authors.forename: Nazia
authors.initials: N
authors.lastname: Quraishi
authors.forename: Amjad
authors.initials: A
authors.lastname: Ali
authors.forename: Ralph T
authors.initials: RT
authors.lastname: Mosley
authors.forename: James R
authors.initials: JR
authors.lastname: Tata
authors.forename: Milton L
authors.initials: ML
authors.lastname: Hammond
authors.forename: James M
authors.initials: JM
authors.lastname: Balkovec
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: Joanne
authors.initials: J
authors.lastname: Williamson
authors.forename: Douglas K
authors.initials: DK
authors.lastname: Miller
authors.forename: Ting-Ting D
authors.initials: TT
authors.lastname: Yamin
authors.forename: Chris M
authors.initials: CM
authors.lastname: Thompson
authors.forename: Edward A
authors.initials: EA
authors.lastname: O'Neill
authors.forename: Dennis
authors.initials: D
authors.lastname: Zaller
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
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001643:Bridged Bicyclo Compounds / Q000737:chemistry*; D045744:Cell Line, Tumor; D005938:Glucocorticoids / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D051379:Mice; D008956:Models, Chemical; D008958:Models, Molecular; D011720:Pyrazoles / Q000737:chemistry*; D011965:Receptors, Glucocorticoid / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001643:Bridged Bicyclo Compounds; D005938:Glucocorticoids; D008024:Ligands; D011720:Pyrazoles; D011965:Receptors, Glucocorticoid; C031280:pyrazole