title: Discovery of XEN445: a potent and selective endothelial lipase inhibitor raises plasma HDL-cholesterol concentration in mice.
abstract: Endothelial lipase (EL) activity has been implicated in HDL metabolism and in atherosclerotic plaque development; inhibitors are proposed to be efficacious in the treatment of dyslipidemia related cardiovascular disease. We describe here the discovery of a novel class of anthranilic acids EL inhibitors. XEN445 (compound 13) was identified as a potent and selective EL inhibitor, that showed good ADME and PK properties, and demonstrated in vivo efficacy in raising plasma HDLc concentrations in mice.
authors.affiliation: Xenon Pharmaceuticals Inc, 200-3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada. Electronic address: ssun@xenon-pharma.com.
authors.forename: Shaoyi
authors.initials: S
authors.lastname: Sun
authors.forename: Richard
authors.initials: R
authors.lastname: Dean
authors.forename: Qi
authors.initials: Q
authors.lastname: Jia
authors.forename: Alla
authors.initials: A
authors.lastname: Zenova
authors.forename: Jing
authors.initials: J
authors.lastname: Zhong
authors.forename: Celene
authors.initials: C
authors.lastname: Grayson
authors.forename: Clark
authors.initials: C
authors.lastname: Xie
authors.forename: Andrea
authors.initials: A
authors.lastname: Lindgren
authors.forename: Pritpaul
authors.initials: P
authors.lastname: Samra
authors.forename: Luis
authors.initials: L
authors.lastname: Sojo
authors.forename: Margaret
authors.initials: M
authors.lastname: van Heek
authors.forename: Linus
authors.initials: L
authors.lastname: Lin
authors.forename: David
authors.initials: D
authors.lastname: Percival
authors.forename: Jian-Min
authors.initials: JM
authors.lastname: Fu
authors.forename: Michael D
authors.initials: MD
authors.lastname: Winther
authors.forename: Zaihui
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001565:Benzoates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008076:Cholesterol, HDL / Q000097:blood* / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008049:Lipase / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015394:Molecular Structure; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C000591624:2-(3-(pyridin-2-ylmethoxy)pyrrolidin-1-yl)-5-(trifluoromethyl)benzoic acid; D001565:Benzoates; D008076:Cholesterol, HDL; D004791:Enzyme Inhibitors; D011759:Pyrrolidines; D008049:Lipase
keywords: Anthranilic acid; Cardiovascular disease; Endothelial lipase inhibitors; HDL cholesterol