title: A strategy of employing aminoheterocycles as amide mimics to identify novel, potent and bioavailable soluble epoxide hydrolase inhibitors.
abstract: Distinct from previously reported urea and amide inhibitors of soluble epoxide hydrolase (sEH), a novel class of inhibitors were rationally designed based on the X-ray structure of this enzyme and known amide inhibitors. The structure-activity relationship (SAR) study was focused on improving the sEH inhibitory activity. Aminobenzisoxazoles emerged to be the optimal series, of which a potent human sEH inhibitor 7t was identified with a good pharmacokinetics (PK) profile. The strategy of employing aminoheterocycles as amide replacements may represent a general approach to develop mimics of known hydrolase or protease inhibitors containing an amide moiety.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA. hong_shen@merck.com
authors.forename: Hong C
authors.initials: HC
authors.lastname: Shen
authors.forename: Fa-Xiang
authors.initials: FX
authors.lastname: Ding
authors.forename: Qiaolin
authors.initials: Q
authors.lastname: Deng
authors.forename: Suoyu
authors.initials: S
authors.lastname: Xu
authors.forename: Xinchun
authors.initials: X
authors.lastname: Tong
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhang
authors.forename: Yuli
authors.initials: Y
authors.lastname: Chen
authors.forename: Gaochao
authors.initials: G
authors.lastname: Zhou
authors.forename: Lee-Yuh
authors.initials: LY
authors.lastname: Pai
authors.forename: Magdalena
authors.initials: M
authors.lastname: Alonso-Galicia
authors.forename: Sophie
authors.initials: S
authors.lastname: Roy
authors.forename: Bei
authors.initials: B
authors.lastname: Zhang
authors.forename: James R
authors.initials: JR
authors.lastname: Tata
authors.forename: Joel P
authors.initials: JP
authors.lastname: Berger
authors.forename: Steven L
authors.initials: SL
authors.lastname: Colletti
mesh_terms: D000577:Amides / Q000737:chemistry*; D000814:Aniline Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006574:Heterocyclic Compounds, 2-Ring / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011485:Protein Binding; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D000814:Aniline Compounds; D004791:Enzyme Inhibitors; D006574:Heterocyclic Compounds, 2-Ring; D007555:Isoxazoles; D004851:Epoxide Hydrolases