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

被引：8

作者：

Bagley, Mark C. ^{[1
]}

Davis, Terence ^{[2
]}

Dix, Matthew C. ^{[1
]}

Murziani, Paola G. S. ^{[1
]}

Rokicki, Michal J. ^{[2
]}

Kipling, David ^{[2
]}

机构：

[1] Cardiff Univ, Sch Chem, Cardiff CF10 3AT, S Glam, Wales

[2] Cardiff Univ, Sch Med, Dept Pathol, Cardiff CF14 4XN, S Glam, Wales

来源：

FUTURE MEDICINAL CHEMISTRY | 2010年 / 2卷 / 02期

基金：

英国生物技术与生命科学研究理事会; 英国工程与自然科学研究理事会;

关键词：

REPLICATIVE SENESCENCE; PROGEROID SYNDROME; KINASE; DISCOVERY; RO3201195; VX-745;

D O I：

10.4155/FMC.09.160

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Background: The pyrazolyl ketone motif of R03201195, 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 beta-ketonitrile and formamidine, to give beta-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.

引用

页码：203 / 213

页数：11

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