Microwave-assisted synthesis of a pyrazolyl ketone library for evaluation as p38 MAPK inhibitors in Werner syndrome cells

Bagley, Mark C, Davis, Terence, Dix, Matthew C, Murziani, Paola Gs, Rokicki, Michal J and Kipling, David (2010) Microwave-assisted synthesis of a pyrazolyl ketone library for evaluation as p38 MAPK inhibitors in Werner syndrome cells. Future Medicinal Chemistry, 2 (2). pp. 203-213. ISSN 1756-8927

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Abstract

Background: The pyrazolyl ketone motif of RO3201195, which exhibits good oral bioavailability and high selectivity for p38 MAPK over other kinases, is a key pharmacophore that could find application in the treatment of Werner syndrome. Results and discussion: Microwave irradiation promotes Knoevenagel condensation of a β-ketonitrile and formamidine, to give β-aminovinyl ketones, and their subsequent cyclocondensation with a subset of hydrazines to provide rapid access to a 24-membered library of pyrazolyl ketones. The library was evaluated in human hTERT-immortalized HCA2 dermal cells and Werner syndrome cells. Conclusion: Four compounds display comparable, if not slightly improved, potency over RO3201195.

Item Type: Article
Schools and Departments: School of Life Sciences > Chemistry
Subjects: Q Science
Depositing User: Deeptima Massey
Date Deposited: 29 Oct 2012 09:32
Last Modified: 14 Mar 2017 02:03
URI: http://sro.sussex.ac.uk/id/eprint/40893

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