Bioorganic & Medicinal Chemistry Letters 2013-07-01

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

Sung Hee Hwang, Aaron T Wecksler, Guodong Zhang, Christophe Morisseau, Long V Nguyen, Samuel H Fu, Bruce D Hammock

文献索引：Bioorg. Med. Chem. Lett. 23(13) , 3732-7, (2013)

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摘要

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.Copyright © 2013 Elsevier Ltd. All rights reserved.