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

journal contribution
posted on 2023-06-08, 12:30 authored by Mark BagleyMark Bagley, Terence Davis, Matthew C Dix, Paola Gs Murziani, Michal J Rokicki, David Kipling
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 ß-ketonitrile and formamidine, to give ß-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.

History

Publication status

  • Published

Journal

Future Medicinal Chemistry

ISSN

1756-8927

Publisher

Future Science

Issue

2

Volume

2

Page range

203-213

Department affiliated with

  • Chemistry Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2012-10-29

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