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

John Wityak; 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

doi:10.1016/j.bmcl.2004.01.012

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.

Authors

John Wityak¹, 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

Affiliation

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.

MeSH terms

Animals
Butadienes / chemical synthesis*
COS Cells
Chemistry, Pharmaceutical / methods*
Chlorocebus aethiops
Enzyme Inhibitors / chemical synthesis*
Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors*
Mitogen-Activated Protein Kinase Kinases / metabolism
Nitriles / chemical synthesis*
Structure-Activity Relationship

Substances

Butadienes
Enzyme Inhibitors
Nitriles
U 0126
Mitogen-Activated Protein Kinase Kinases