The discovery of the benzhydroxamate MEK inhibitors CI-1040 and PD 0325901

…, SA Przybranowski, J Sebolt-Leopold…

Index: Barrett, Stephen D.; Bridges, Alexander J.; Dudley, David T.; Saltiel, Alan R.; Fergus, James H.; Flamme, Cathlin M.; Delaney, Amy M.; Kaufman, Michael; LePage, Sophie; Leopold, Wilbur R.; Przybranowski, Sally A.; Sebolt-Leopold, Judith; Van Becelaere, Keri; Doherty, Annette M.; Kennedy, Robert M.; Marston, Dan; Howard Jr., W. Allen; Smith, Yvonne; Warmus, Joseph S.; Tecle, Haile Bioorganic and Medicinal Chemistry Letters, 2008 , vol. 18, # 24 p. 6501 - 6504

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Citation Number: 164

Abstract

A novel series of benzhydroxamate esters derived from their precursor anthranilic acids have been prepared and have been identified as potent MEK inhibitors. 2-(2-Chloro-4-iodo- phenylamino)-N-cyclopropylmethoxy-3, 4-difluoro-benzamide, CI-1040, was the first MEK inhibitor to demonstrate in vivo activity in preclinical animal models and subsequently became the first MEK inhibitor to enter clinical trial. CI-1040 suffered however from poor ...