title: Discovery and optimisation of potent, selective, ethanolamine inhibitors of bacterial phenylalanyl tRNA synthetase.
abstract: High throughput screening of Staphylococcus aureus phenylalanyl tRNA synthetase (FRS) identified ethanolamine 1 as a sub-micromolar hit. Optimisation studies led to the enantiospecific lead 64, a single-figure nanomolar inhibitor. The inhibitor series shows selectivity with respect to the mammalian enzyme and the potential for broad spectrum bacterial FRS inhibition.
authors.affiliation: GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK. richard.l.jarvest@gsk.com
authors.forename: Richard L
authors.initials: RL
authors.lastname: Jarvest
authors.forename: Symon G
authors.initials: SG
authors.lastname: Erskine
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Forrest
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Fosberry
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Hibbs
authors.forename: Joanna J
authors.initials: JJ
authors.lastname: Jones
authors.forename: Peter J
authors.initials: PJ
authors.lastname: O'Hanlon
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Sheppard
authors.forename: Angela
authors.initials: A
authors.lastname: Worby
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D004983:Ethanolamines / Q000138:chemical synthesis* / Q000494:pharmacology*; D007700:Kinetics; D008322:Mammals; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D010652:Phenylalanine-tRNA Ligase / Q000037:antagonists & inhibitors*; D012680:Sensitivity and Specificity; D013211:Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D004983:Ethanolamines; D010652:Phenylalanine-tRNA Ligase