title: Novel N-arylpyrazolo[3,2-c]-based ligands for the glucocorticoid receptor: receptor binding and in vivo activity.
abstract: A novel series of selective ligands for the human glucocorticoid receptor (hGR) are described. Preliminary structure-activity relationships were focused on substitution at C-1 and indicated a preference for 3-, 4-, and 5-substituted aromatic and benzylic groups. The resulting analogues, e.g., 18 and 34, exhibited excellent affinity for hGR (IC(50) 1.9 nM and 2.8 nM, respectively) and an interesting partial agonist profile in functional assays of transactivation (tyrosine aminotransferase, TAT, and glutamine synthetase, GS) and transrepression (IL-6). The most potent compounds described in this study were the tertiary alcohol derivatives 21 and 25. These candidates showed highly efficacious IL-6 inhibition versus dexamethasone. The thiophenyl analogue 25 was evaluated in vivo in the mouse LPS challenge model and showed an ED(50) = 4.0 mg/kg, compared to 0.5 mg/kg for prednisolone in the same assay.
authors.affiliation: Departments of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, New Jersey 07065, USA. amjad_ali@merck.com
authors.forename: Amjad
authors.initials: A
authors.lastname: Ali
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Thompson
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: Nazia
authors.initials: N
authors.lastname: Quraishi
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
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: Chris M
authors.initials: CM
authors.lastname: Thompson
authors.forename: Dennis M
authors.initials: DM
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; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D018360:Crystallography, X-Ray; D004790:Enzyme Induction; D005260:Female; D005974:Glutamate-Ammonia Ligase / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007191:Indazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D008968:Molecular Conformation; D020033:Protein Isoforms / Q000819:agonists / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D011965:Receptors, Glucocorticoid / Q000819:agonists / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D014444:Tyrosine Transaminase / Q000096:biosynthesis / Q000235:genetics; D000093242:Interleukin-6 Inhibitors
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D005974:Glutamate-Ammonia Ligase; D007191:Indazoles; D008024:Ligands; D020033:Protein Isoforms; D011720:Pyrazoles; D011965:Receptors, Glucocorticoid; D013876:Thiophenes; D014409:Tumor Necrosis Factor-alpha; D014444:Tyrosine Transaminase; D000093242:Interleukin-6 Inhibitors; C486787:1-(3-thienyl)(1-(4-fluorophenyl)-4a-methyl-4,4a,5,6,7,8-hexahydro-1H-benzo(f)indazol-5-yl)methanone; C486786:1-(4-fluorophenyl)-1-(1-(4-fluorophenyl)-4a-methyl-4,4a,5,6,7,8-hexahydro-1H-benzo(f)indazol-5-yl)ethanol