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Bioorg Med Chem Lett. 2013 Jul 1;23(13):3732-7. doi: 10.1016/j.bmcl.2013.05.011. Epub 2013 May 15.

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

Author information

1
Department of Entomology and UC Davis Comprehensive Cancer Center, University of California, Davis, One Shields Avenue, Davis, CA 95616-8584, USA.

Abstract

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.

PMID:
23726028
PMCID:
PMC3744640
DOI:
10.1016/j.bmcl.2013.05.011
[Indexed for MEDLINE]
Free PMC Article

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