Beyond U0126. Dianion chemistry leading to the rapid synthesis of a series of potent MEK inhibitors.
Employing phenylmalonitrile dianion chemistry, a large number of analogues of MEK inhibitor lead SH053 (IC(50)=140 nM) were rapidly synthesized leading to single digit nM inhibitors, displaying submicromolar AP-1 transcription inhibition in COS-7 cells. Compound 41, exhibiting a MEK IC(50)=12 nM showed ip activity in a TPA-induced ear edema model with an ED(50)=5 mg/kg.
Bristol-Myers Squibb Pharmaceuticals Research Institute, PO Box 4000, Princeton, NJ 08543-4000, USA.
John
J
Wityak
Frank W
FW
Hobbs
Daniel S
DS
Gardner
Joseph B
JB
Santella
Joseph J
JJ
Petraitis
Jung-Hui
JH
Sun
Margaret F
MF
Favata
Andrea J
AJ
Daulerio
Kurumi Y
KY
Horiuchi
Robert A
RA
Copeland
Peggy A
PA
Scherle
Bruce D
BD
Jaffe
James M
JM
Trzaskos
Ronald L
RL
Magolda
George L
GL
Trainor
John V
JV
Duncia
D000818:Animals; D002070:Butadienes / Q000138:chemical synthesis*; D019556:COS Cells; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D002522:Chlorocebus aethiops; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009570:Nitriles / Q000138:chemical synthesis*; D013329:Structure-Activity Relationship
D002070:Butadienes; D004791:Enzyme Inhibitors; D009570:Nitriles; C113580:U 0126; D020929:Mitogen-Activated Protein Kinase Kinases