3,5-Bis(trifluoromethyl)pyrazoles: a novel class of NFAT transcription factor regulator.
A series of bis(trifluoromethyl)pyrazoles (BTPs) has been found to be a novel inhibitor of cytokine production. Identified initially as inhibitors of IL-2 synthesis, the BTPs have been optimized in this regard and even inhibit IL-2 production with a 10-fold enhancement over cyclosporine in an ex vivo assay. Additionally, the BTPs show inhibition of IL-4, IL-5, IL-8, and eotaxin production. Unlike the IL-2 inhibitors, cyclosporine and FK506, the BTPs do not directly inhibit the dephosphorylation of NFAT by calcineurin.
Djuric
S W
SW
Immunological Diseases Research, Abbott Laboratories, 200 Abbott Park Road, Abbott Park, Illinois 60064-6217, USA. stevan.w.djuric@abbott.com
BaMaung
N Y
NY
Basha
A
A
Liu
H
H
Luly
J R
JR
Madar
D J
DJ
Sciotti
R J
RJ
Tu
N P
NP
Wagenaar
F L
FL
Wiedeman
P E
PE
Zhou
X
X
Ballaron
S
S
Bauch
J
J
Chen
Y W
YW
Chiou
X G
XG
Fey
T
T
Gauvin
D
D
Gubbins
E
E
Hsieh
G C
GC
Marsh
K C
KC
Mollison
K W
KW
Pong
M
M
Shaughnessy
T K
TK
Sheets
M P
MP
Smith
M
M
Trevillyan
J M
JM
Warrior
U
U
Wegner
C D
CD
Carter
G W
GW
D000818:Animals; D001249:Asthma / Q000188:drug therapy; D002455:Cell Division; D054413:Chemokine CCL11; D019742:Chemokines, CC; D020650:Combinatorial Chemistry Techniques; D016572:Cyclosporine / Q000494:pharmacology; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000378:metabolism*; D017930:Genes, Reporter; D000882:Haplorhini; D006801:Humans; D007166:Immunosuppressive Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015848:Interleukin-5 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016209:Interleukin-8 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D019169:Jurkat Cells; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects; D008156:Luciferases / Q000235:genetics; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011500:Protein Synthesis Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D014157:Transcription Factors / Q000378:metabolism*
C515456:CCL11 protein, human; C515458:Ccl11 protein, rat; D054413:Chemokine CCL11; D019742:Chemokines, CC; D016207:Cytokines; D004268:DNA-Binding Proteins; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D015848:Interleukin-5; D016209:Interleukin-8; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011500:Protein Synthesis Inhibitors; D011720:Pyrazoles; D014157:Transcription Factors; D015847:Interleukin-4; D016572:Cyclosporine; D008156:Luciferases