Synthesis and biological evaluation of novel macrocyclic bis-7-azaindolylmaleimides as potent and highly selective glycogen synthase kinase-3β (GSK-3β) inhibitors

被引:27
作者
Shen, L [1 ]
Prouty, C [1 ]
Conway, BR [1 ]
Westover, L [1 ]
Xu, JZ [1 ]
Look, RA [1 ]
Chen, X [1 ]
Beavers, MP [1 ]
Roberts, J [1 ]
Murray, WV [1 ]
Demarest, KT [1 ]
Kuo, GH [1 ]
机构
[1] Johnson & Johnson Pharmaceut Res & Dev LLC, Drug Discovery Div, Raritan, NJ 08869 USA
关键词
specific inhibitor; kinase; azaindolemaleimide; cross-x11dummy; coupling;
D O I
10.1016/j.bmc.2003.09.047
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Palladium catalyzed cross-coupling reactions were used to synthesize two key intermediates 3 and 5 that resulted in the synthesis of novel series of macrocyclic bis-7-azaindolylmaleimides. Among the three series of macrocycles, the oxygen atom and thiophene containing linkers yielded molecules with higher inhibitory potency at GSK-3beta (K-i = 0.011-0.079 muM) while the nitrogen atom containing linkers yielded molecules with lower potency (K-i = 0.150-> 1 muM). Compound 33 and 36 displayed 1-2 orders of magnitude selectivity at GSK-3beta against CDK2, PKCbetaII, Rsk3 and little or no inhibitions to the other 62 protein kinases. Compound 46 was at least 100-fold more selective towards GSK-30 than PKCbetaII, and it had little or no activity against a panel of 65 protein kinases, almost behaved as a GSK-3beta 'specific inhibitor'. All three compounds showed good potency in GS assay. Molecular docking studies were conducted in an attempt to rationalize the GSK-30 selectivity of azaindolylmaleimides. The high selectivity, inhibitory potency and cellular activities of these non-crown-ether typed molecules may provide them as a valuable pharmacological tools in elucidating the complex roles of GSK-3beta in cell signaling pathways and the potential usage for the treatment of elevated level of GSK-3beta involved diseases. (C) 2003 Elsevier Ltd. All rights reserved.
引用
收藏
页码:1239 / 1255
页数:17
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