期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 64, 期 -, 页码 137-147出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2013.03.038
关键词
Anticancer; Antitumor; PI 3-kinase; Synthesis; ZSTK474
资金
- Auckland Division of the Cancer Society of New Zealand
- Health Research Council of New Zealand
- Maurice Wilkins Centre for Molecular Biodiscovery
- Pathway Therapeutics Inc.
A range of 4-substituted derivatives of the pan class I PI 3-kinase inhibitor 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474) were prepared in a search for more soluble analogs. 4-Aminoalkoxy substituents provided the most potent derivatives, with the 4-O(CH2)(3)NMe2 analog (compound 14) being identified as displaying the best overall activity in combination with good aqueous solubility (25 mg/mL for the hydrochloride salt). This compound was tested in a U87MG xenograft model, but displayed less potency than ZSTK474 as a result of an unfavorable pharmacokinetic profile. (C) 2013 Elsevier Masson SAS. All rights reserved.
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