title: Selection and optimization of hits from a high-throughput phenotypic screen against Trypanosoma cruzi.
abstract: BACKGROUND
  Inhibitors of Trypanosoma cruzi with novel mechanisms of action are urgently required to diversify the current clinical and preclinical pipelines. Increasing the number and diversity of hits available for assessment at the beginning of the discovery process will help to achieve this aim.
  
  
  RESULTS
  We report the evaluation of multiple hits generated from a high-throughput screen to identify inhibitors of T. cruzi and from these studies the discovery of two novel series currently in lead optimization. Lead compounds from these series potently and selectively inhibit growth of T. cruzi in vitro and the most advanced compound is orally active in a subchronic mouse model of T. cruzi infection.
  
  
  CONCLUSIONS
  High-throughput screening of novel compound collections has an important role to play in diversifying the trypanosomatid drug discovery portfolio. A new T. cruzi inhibitor series with good drug-like properties and promising in vivo efficacy has been identified through this process.
authors.affiliation: Epichem Pty Ltd, Murdoch University Campus, South Street, Murdoch, Western Australia 6150, Australia.
authors.forename: Martine
authors.initials: M
authors.lastname: Keenan
authors.forename: Paul W
authors.initials: PW
authors.lastname: Alexander
authors.forename: Jason H
authors.initials: JH
authors.lastname: Chaplin
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Abbott
authors.forename: Hugo
authors.initials: H
authors.lastname: Diao
authors.forename: Zhisen
authors.initials: Z
authors.lastname: Wang
authors.forename: Wayne M
authors.initials: WM
authors.lastname: Best
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Perez
authors.forename: Scott M J
authors.initials: SM
authors.lastname: Cornwall
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Keatley
authors.forename: R C Andrew
authors.initials: RC
authors.lastname: Thompson
authors.forename: Susan A
authors.initials: SA
authors.lastname: Charman
authors.forename: Karen L
authors.initials: KL
authors.lastname: White
authors.forename: Eileen
authors.initials: E
authors.lastname: Ryan
authors.forename: Gong
authors.initials: G
authors.lastname: Chen
authors.forename: Jean-Robert
authors.initials: JR
authors.lastname: Ioset
authors.forename: Thomas W
authors.initials: TW
authors.lastname: von Geldern
authors.forename: Eric
authors.initials: E
authors.lastname: Chatelain
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D014355:Chagas Disease / Q000188:drug therapy / Q000401:mortality; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D004195:Disease Models, Animal; D057166:High-Throughput Screening Assays; D006801:Humans; D051379:Mice; D021261:Parasitic Sensitivity Tests; D051381:Rats; D013329:Structure-Activity Relationship; D015996:Survival Rate; D013997:Time Factors; D014344:Trypanocidal Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D014349:Trypanosoma cruzi / Q000187:drug effects*
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D014344:Trypanocidal Agents; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human