2-Alkylamino- and alkoxy-substituted 2-amino-1,3,4-oxadiazoles-O-Alkyl benzohydroxamate esters replacements retain the desired inhibition and selectivity against MEK (MAP ERK kinase)

  • Bioorg Med Chem Lett. 2008 Dec 1;18(23):6171-4. doi: 10.1016/j.bmcl.2008.10.015.
Joseph S Warmus  1 ,  Cathlin Flamme ,  Lu Yan Zhang ,  Stephen Barrett ,  Alexander Bridges ,  Huifen Chen ,  Richard Gowan ,  Michael Kaufman ,  Judy Sebolt-Leopold ,  Wilbur Leopold ,  Ronald Merriman ,  Jeffrey Ohren ,  Alexander Pavlovsky ,  Sally Przybranowski ,  Haile Tecle ,  Heather Valik ,  Christopher Whitehead ,  Erli Zhang
Affiliations
  • 1. Department of Chemistry, Pfizer Global Research and Development, Ann Arbor, MI 48105, USA. [email protected]
PMID: 18951019 DOI: 10.1016/j.bmcl.2008.10.015
Abstract

This paper reports a second generation MEK Inhibitor. The previously reported potent and efficacious MEK Inhibitor, PD-184352 (CI-1040), contains an integral hydroxamate moiety. This compound suffered from less than ideal solubility and metabolic stability. An oxadiazole moiety behaves as a bioisostere for the hydroxamate group, leading to a more metabolically stable and efficacious MEK Inhibitor.