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

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.

• Authors: Mark C Bagley, Terence Davis, Matthew C Dix, Paola G S Murziani, Michal J Rokicki, David Kipling
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 18 Issue 13 Pg. 3745-8 (Jul 01 2008) ISSN: 1464-3405 [Electronic] England
• PMID: 18539026 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

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