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. Epub 2008 Oct 7.

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.

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Benzamides / chemistry
  • Benzamides / pharmacology*
  • Colonic Neoplasms / chemically induced
  • Colonic Neoplasms / drug therapy
  • Combinatorial Chemistry Techniques
  • Drug Screening Assays, Antitumor
  • Esters
  • Humans
  • Hydroxamic Acids / chemical synthesis*
  • Hydroxamic Acids / chemistry
  • Hydroxamic Acids / pharmacology*
  • Microsomes, Liver / drug effects
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors*
  • Molecular Structure
  • Oxadiazoles / chemical synthesis*
  • Oxadiazoles / chemistry
  • Oxadiazoles / pharmacology*
  • Structure-Activity Relationship

Substances

  • 2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide
  • Antineoplastic Agents
  • Benzamides
  • Esters
  • Hydroxamic Acids
  • Oxadiazoles
  • Mitogen-Activated Protein Kinase Kinases