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.
Wityak
John
J
Bristol-Myers Squibb Pharmaceuticals Research Institute, PO Box 4000, Princeton, NJ 08543-4000, USA.
Hobbs
Frank W
FW
Gardner
Daniel S
DS
Santella
Joseph B
JB
Petraitis
Joseph J
JJ
Sun
Jung-Hui
JH
Favata
Margaret F
MF
Daulerio
Andrea J
AJ
Horiuchi
Kurumi Y
KY
Copeland
Robert A
RA
Scherle
Peggy A
PA
Jaffe
Bruce D
BD
Trzaskos
James M
JM
Magolda
Ronald L
RL
Trainor
George L
GL
Duncia
John V
JV
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