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

  • Bioorg Med Chem Lett. 2004 Mar 22;14(6):1483-6. doi: 10.1016/j.bmcl.2004.01.012.
John Wityak  1 ,  Frank W Hobbs ,  Daniel S Gardner ,  Joseph B Santella 3rd ,  Joseph J Petraitis ,  Jung-Hui Sun ,  Margaret F Favata ,  Andrea J Daulerio ,  Kurumi Y Horiuchi ,  Robert A Copeland ,  Peggy A Scherle ,  Bruce D Jaffe ,  James M Trzaskos ,  Ronald L Magolda ,  George L Trainor ,  John V Duncia
Affiliations
  • 1. Bristol-Myers Squibb Pharmaceuticals Research Institute, PO Box 4000, Princeton, NJ 08543-4000, USA.
PMID: 15006386 DOI: 10.1016/j.bmcl.2004.01.012
Abstract

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.