title: Discovery of potent, selective sulfonylfuran urea endothelial lipase inhibitors.
abstract: Endothelial lipase (EL) activity has been implicated in HDL catabolism, vascular inflammation, and atherogenesis, and inhibitors are therefore expected to be useful for the treatment of cardiovascular disease. Sulfonylfuran urea 1 was identified in a high-throughput screening campaign as a potent and non-selective EL inhibitor. A lead optimization effort was undertaken to improve potency and selectivity, and modifications leading to improved LPL selectivity were identified. Radiolabeling studies were undertaken to establish the mechanism of action for these inhibitors, which were ultimately demonstrated to be irreversible inhibitors.
authors.affiliation: Department of Chemistry, Cardiovascular and Urogenital Center of Excellence in Drug Discovery, GlaxoSmithKline, UW2430, King of Prussia, PA 19406, USA. krista.b.goodman@gsk.com
authors.forename: Krista B
authors.initials: KB
authors.lastname: Goodman
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bury
authors.forename: Mui
authors.initials: M
authors.lastname: Cheung
authors.forename: Maria A
authors.initials: MA
authors.lastname: Cichy-Knight
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Dowdell
authors.forename: Allison K
authors.initials: AK
authors.lastname: Dunn
authors.forename: Dennis
authors.initials: D
authors.lastname: Lee
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Lieby
authors.forename: Michael L
authors.initials: ML
authors.lastname: Moore
authors.forename: Daryl A
authors.initials: DA
authors.lastname: Scherzer
authors.forename: Deyou
authors.initials: D
authors.lastname: Sha
authors.forename: Dominic P
authors.initials: DP
authors.lastname: Suarez
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Murphy
authors.forename: Mark R
authors.initials: MR
authors.lastname: Harpel
authors.forename: Eric S
authors.initials: ES
authors.lastname: Manas
authors.forename: Dean E
authors.initials: DE
authors.lastname: McNulty
authors.forename: Roland S
authors.initials: RS
authors.lastname: Annan
authors.forename: Rosalie E
authors.initials: RE
authors.lastname: Matico
authors.forename: Benjamin K
authors.initials: BK
authors.lastname: Schwartz
authors.forename: John J
authors.initials: JJ
authors.lastname: Trill
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Sweitzer
authors.forename: Da-Yuan
authors.initials: DY
authors.lastname: Wang
authors.forename: Paul M
authors.initials: PM
authors.lastname: Keller
authors.forename: John A
authors.initials: JA
authors.lastname: Krawiec
authors.forename: Michael C
authors.initials: MC
authors.lastname: Jaye
mesh_terms: D000818:Animals; D002318:Cardiovascular Diseases / Q000188:drug therapy; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D004727:Endothelium / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D005663:Furans; D006801:Humans; D008049:Lipase / Q000037:antagonists & inhibitors*; D013453:Sulfonylurea Compounds / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D005663:Furans; D013453:Sulfonylurea Compounds; D008049:Lipase