Synthesis and biological evaluation of sorafenib- and regorafenib-like sEH inhibitors

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• 作者：Sung Hee Hwang ; Aaron T. Wecksler ; Guodong Zhang ; Christophe Morisseau ; Long V. Nguyen ; Samuel H. Fu ; Bruce D. Hammock ; ^{bdhammock@ucdavis.edu}
• 关键词：HCC ; hepatocellular carcinoma ; RCC ; renal cell carcinoma ; GI50 ; concentration required to inhibit cell growth by 50 % ; EpFAs ; epoxygenated fatty acids ; t-CUPM ; trans-4-{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-ureido]-cyclohexyloxy}-pyridine-2-carboxylic a
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2013
• 出版时间：1 July, 2013
• 年：2013
• 卷：23
• 期：13
• 页码：3732-3737
• 全文大小：722 K

文摘

To reduce the pro-angiogenic effects of sEH inhibition, a structure-activity relationship (SAR) study was performed by incorporating structural features of the anti-angiogenic multi-kinase inhibitor sorafenib into soluble epoxide hydrolase (sEH) inhibitors. The structural modifications of this series of molecules enabled the altering of selectivity towards the pro-angiogenic kinases C-RAF and vascular endothelial growth factor receptor-2 (VEGFR-2), while retaining their sEH inhibition. As a result, sEH inhibitors with greater potency against C-RAF and VEGFR-2 were obtained. Compound 4 (t-CUPM) possesses inhibition potency higher than sorafenib towards sEH but similar against C-RAF and VEGFR-2. Compound 7 (t-CUCB) selectively inhibits sEH, while inhibiting HUVEC cell proliferation, a potential anti-angiogenic property, without liver cancer cell cytotoxicity. The data presented suggest a potential rational approach to control the angiogenic responses stemming from sEH inhibition.