title: Discovery of a novel class of orally active trypanocidal N-myristoyltransferase inhibitors.
abstract: N-Myristoyltransferase (NMT) represents a promising drug target for human African trypanosomiasis (HAT), which is caused by the parasitic protozoa Trypanosoma brucei. We report the optimization of a high throughput screening hit (1) to give a lead molecule DDD85646 (63), which has potent activity against the enzyme (IC(50) = 2 nM) and T. brucei (EC(50) = 2 nM) in culture. The compound has good oral pharmacokinetics and cures rodent models of peripheral HAT infection. This compound provides an excellent tool for validation of T. brucei NMT as a drug target for HAT as well as a valuable lead for further optimization.
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee, DD1 5EH, U.K.
authors.forename: Stephen
authors.initials: S
authors.lastname: Brand
authors.forename: Laura A T
authors.initials: LA
authors.lastname: Cleghorn
authors.forename: Stuart P
authors.initials: SP
authors.lastname: McElroy
authors.forename: David A
authors.initials: DA
authors.lastname: Robinson
authors.forename: Victoria C
authors.initials: VC
authors.lastname: Smith
authors.forename: Irene
authors.initials: I
authors.lastname: Hallyburton
authors.forename: Justin R
authors.initials: JR
authors.lastname: Harrison
authors.forename: Neil R
authors.initials: NR
authors.lastname: Norcross
authors.forename: Daniel
authors.initials: D
authors.lastname: Spinks
authors.forename: Tracy
authors.initials: T
authors.lastname: Bayliss
authors.forename: Suzanne
authors.initials: S
authors.lastname: Norval
authors.forename: Laste
authors.initials: L
authors.lastname: Stojanovski
authors.forename: Leah S
authors.initials: LS
authors.lastname: Torrie
authors.forename: Julie A
authors.initials: JA
authors.lastname: Frearson
authors.forename: Ruth
authors.initials: R
authors.lastname: Brenk
authors.forename: Alan H
authors.initials: AH
authors.lastname: Fairlamb
authors.forename: Michael A J
authors.initials: MA
authors.lastname: Ferguson
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Read
authors.forename: Paul G
authors.initials: PG
authors.lastname: Wyatt
authors.forename: Ian H
authors.initials: IH
authors.lastname: Gilbert
mesh_terms: D000217:Acyltransferases / Q000037:antagonists & inhibitors*; D000284:Administration, Oral; D000631:Aminopyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D016208:Databases, Factual; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D021261:Parasitic Sensitivity Tests; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D014346:Trypanosoma brucei brucei / Q000187:drug effects; D014353:Trypanosomiasis, African / Q000188:drug therapy; D000096926:Benzenesulfonamides
chemical_list: D000217:Acyltransferases; D000631:Aminopyridines; D013449:Sulfonamides; D014344:Trypanocidal Agents; C549249:DDD 85646; D000096926:Benzenesulfonamides; C050480:glycylpeptide N-tetradecanoyltransferase