Microwave-assisted synthesis of 5-aminopyrazol-4-yl ketones and the p38(MAPK) inhibitor RO3201195 for study in Werner syndrome cells

Bioorg Med Chem Lett. 2008 Jul 1;18(13):3745-8. doi: 10.1016/j.bmcl.2008.05.037. Epub 2008 May 16.

Abstract

5-Aminopyrazol-4-yl ketones are prepared rapidly and efficiently using microwave dielectric heating from beta-ketonitriles by treatment with N,N'-diphenylformamidine followed by heterocyclocondensation by irradiation with a hydrazine. The inhibitory activity of RO3201195 prepared by this methodology was confirmed in hTERT-immortalized HCA2 and WS dermal fibroblasts at 200nM concentration, both by ELISA and immunoblot assay, and displays excellent kinase selectivity for p38alpha MAPK over the related stress-activated kinase JNK.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Chemistry, Pharmaceutical / methods
  • Enzyme Activation
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Inhibitory Concentration 50
  • Ketones / chemistry*
  • MAP Kinase Kinase 4 / metabolism
  • Microwaves*
  • Models, Chemical
  • Naphthalenes / chemistry
  • Nitriles / chemistry
  • Protein Isoforms
  • Pyrazoles / chemical synthesis*
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology
  • p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

  • 5-amino-1-(4-fluorophenyl)-4-(3-(2,3-dihydroxypropoxy)benzoyl)pyrazole
  • Enzyme Inhibitors
  • Ketones
  • Naphthalenes
  • Nitriles
  • Protein Isoforms
  • Pyrazoles
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 4
  • doramapimod