Beyond U0126. Dianion chemistry leading to the rapid synthesis of a series of potent MEK inhibitors

J Wityak, FW Hobbs, DS Gardner, JB Santella…

Index: Wityak, John; Hobbs, Frank W.; Gardner, Daniel S.; Santella III, Joseph B.; Petraitis, Joseph J.; Sun, Jung-Hui; Favata, Margaret F.; Daulerio, Andrea J.; Horiuchi, Kurumi Y.; Copeland, Robert A.; Scherle, Peggy A.; Jaffe, Bruce D.; Trzaskos, James M.; Magolda, Ronald L.; Trainor, George L.; Duncia, John V. Bioorganic and Medicinal Chemistry Letters, 2004 , vol. 14, # 6 p. 1483 - 1486

Full Text: HTML

Citation Number: 27

Abstract

Employing phenylmalonitrile dianion chemistry, a large number of analogues of MEK inhibitor lead SH053 (IC50= 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 IC50= 12 nM showed ip activity in a TPA-induced ear edema model with an ED50= 5 mg/kg.