title: Discovery of 1-(1,3,5-triazin-2-yl)piperidine-4-carboxamides as inhibitors of soluble epoxide hydrolase.
abstract: 1-(1,3,5-Triazin-yl)piperidine-4-carboxamide inhibitors of soluble epoxide hydrolase were identified from high through-put screening using encoded library technology. The triazine heterocycle proved to be a critical functional group, essential for high potency and P450 selectivity. Phenyl group substitution was important for reducing clearance, and establishing good oral exposure. Based on this lead optimization work, 1-[4-methyl-6-(methylamino)-1,3,5-triazin-2-yl]-N-{[[4-bromo-2-(trifluoromethoxy)]-phenyl]methyl}-4-piperidinecarboxamide (27) was identified as a useful tool compound for in vivo investigation. Robust effects on a serum biomarker, 9, 10-epoxyoctadec-12(Z)-enoic acid (the epoxide derived from linoleic acid) were observed, which provided evidence of robust in vivo target engagement and the suitability of 27 as a tool compound for study in various disease models.
authors.affiliation: Department of Chemistry, Heart Failure Disease Performance Unit, Metabolic Pathways and Cardiovascular Therapeutic Area Unit, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, PA 19406, USA.
authors.forename: Reema K
authors.initials: RK
authors.lastname: Thalji
authors.forename: Jeff J
authors.initials: JJ
authors.lastname: McAtee
authors.forename: Svetlana
authors.initials: S
authors.lastname: Belyanskaya
authors.forename: Martin
authors.initials: M
authors.lastname: Brandt
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Brown
authors.forename: Melissa H
authors.initials: MH
authors.lastname: Costell
authors.forename: Yun
authors.initials: Y
authors.lastname: Ding
authors.forename: Jason W
authors.initials: JW
authors.lastname: Dodson
authors.forename: Steve H
authors.initials: SH
authors.lastname: Eisennagel
authors.forename: Rusty E
authors.initials: RE
authors.lastname: Fries
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Gross
authors.forename: Mark R
authors.initials: MR
authors.lastname: Harpel
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Holt
authors.forename: David I
authors.initials: DI
authors.lastname: Israel
authors.forename: Larry J
authors.initials: LJ
authors.lastname: Jolivette
authors.forename: Daniel
authors.initials: D
authors.lastname: Krosky
authors.forename: Hu
authors.initials: H
authors.lastname: Li
authors.forename: Quinn
authors.initials: Q
authors.lastname: Lu
authors.forename: Tracy
authors.initials: T
authors.lastname: Mandichak
authors.forename: Theresa
authors.initials: T
authors.lastname: Roethke
authors.forename: Christine G
authors.initials: CG
authors.lastname: Schnackenberg
authors.forename: Benjamin
authors.initials: B
authors.lastname: Schwartz
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Shewchuk
authors.forename: Wensheng
authors.initials: W
authors.lastname: Xie
authors.forename: David J
authors.initials: DJ
authors.lastname: Behm
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Douglas
authors.forename: Ami L
authors.initials: AL
authors.lastname: Shaw
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Marino
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; D010880:Piperidines; D014227:Triazines; D004851:Epoxide Hydrolases