Novel glucocorticoids containing a 6,5-bicyclic core fused to a pyrazole ring: synthesis, in vitro profile, molecular modeling studies, and in vivo experiments.
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.
Thompson
Christopher F
CF
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA. christopher_thompson@merck.com
Quraishi
Nazia
N
Ali
Amjad
A
Mosley
Ralph T
RT
Tata
James R
JR
Hammond
Milton L
ML
Balkovec
James M
JM
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
Yamin
Ting-Ting D
TT
Thompson
Chris M
CM
O'Neill
Edward A
EA
Zaller
Dennis
D
Forrest
Michael J
MJ
Carballo-Jane
Ester
E
Luell
Silvi
S
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
D000970:Antineoplastic Agents; D001643:Bridged Bicyclo Compounds; D005938:Glucocorticoids; D008024:Ligands; D011720:Pyrazoles; D011965:Receptors, Glucocorticoid; C031280:pyrazole