Novel N-arylpyrazolo[3,2-c]-based ligands for the glucocorticoid receptor: receptor binding and in vivo activity.
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.
Ali
Amjad
A
Departments of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, New Jersey 07065, USA. amjad_ali@merck.com
Thompson
Christopher F
CF
Balkovec
James M
JM
Graham
Donald W
DW
Hammond
Milton L
ML
Quraishi
Nazia
N
Tata
James R
JR
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
Joanne
J
Miller
Douglas K
DK
Thompson
Chris M
CM
Zaller
Dennis M
DM
Forrest
Michael J
MJ
Carballo-Jane
Ester
E
Luell
Silvi
S
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
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