title: Synthesis and biological evaluation of sorafenib- and regorafenib-like sEH inhibitors.
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.
authors.affiliation: Department of Entomology and UC Davis Comprehensive Cancer Center, University of California, Davis, One Shields Avenue, Davis, CA 95616-8584, USA.
authors.forename: Sung Hee
authors.initials: SH
authors.lastname: Hwang
authors.forename: Aaron T
authors.initials: AT
authors.lastname: Wecksler
authors.forename: Guodong
authors.initials: G
authors.lastname: Zhang
authors.forename: Christophe
authors.initials: C
authors.lastname: Morisseau
authors.forename: Long V
authors.initials: LV
authors.lastname: Nguyen
authors.forename: Samuel H
authors.initials: SH
authors.lastname: Fu
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D015394:Molecular Structure; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012995:Solubility; D000077157:Sorafenib; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D010671:Phenylurea Compounds; D011725:Pyridines; C559147:regorafenib; D009536:Niacinamide; D000077157:Sorafenib; D004851:Epoxide Hydrolases