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

Bagley, Mark Christopher, Davis, Terence ORCID: https://orcid.org/0000-0003-2780-0262, Dix, Matthew Charles, Murziani, Paola G. S., Rokicki, Michal Jaroslaw and Kipling, David Glyn 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. 10.4155/fmc.09.160

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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
Date Type:	Publication
Status:	Published
Schools:	Chemistry Medicine
Subjects:	Q Science > QD Chemistry R Medicine > R Medicine (General)
Publisher:	Future Science Ltd
ISSN:	1756-8919
Last Modified:	14 Dec 2022 02:14
URI:	https://orca.cardiff.ac.uk/id/eprint/21999

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