title: Candidate selection and preclinical evaluation of N-tert-butyl isoquine (GSK369796), an affordable and effective 4-aminoquinoline antimalarial for the 21st century.
abstract: N-tert-Butyl isoquine (4) (GSK369796) is a 4-aminoquinoline drug candidate selected and developed as part of a public-private partnership between academics at Liverpool, MMV, and GSK pharmaceuticals. This molecule was rationally designed based on chemical, toxicological, pharmacokinetic, and pharmacodynamic considerations and was selected based on excellent activity against Plasmodium falciparum in vitro and rodent malaria parasites in vivo. The optimized chemistry delivered this novel synthetic quinoline in a two-step procedure from cheap and readily available starting materials. The molecule has a full industry standard preclinical development program allowing first into humans to proceed. Employing chloroquine (1) and amodiaquine (2) as comparator molecules in the preclinical plan, the first preclinical dossier of pharmacokinetic, toxicity, and safety pharmacology has also been established for the 4-aminoquinoline antimalarial class. These studies have revealed preclinical liabilities that have never translated into the human experience. This has resulted in the availability of critical information to other drug development teams interested in developing antimalarials within this class.
authors.affiliation: Department of Chemistry, University of Liverpool, Liverpool, United Kingdom. p.m.oneill01@liv.ac.uk
authors.forename: Paul M
authors.initials: PM
authors.lastname: O'Neill
authors.forename: B Kevin
authors.initials: BK
authors.lastname: Park
authors.forename: Alison E
authors.initials: AE
authors.lastname: Shone
authors.forename: James L
authors.initials: JL
authors.lastname: Maggs
authors.forename: Phillip
authors.initials: P
authors.lastname: Roberts
authors.forename: Paul A
authors.initials: PA
authors.lastname: Stocks
authors.forename: Giancarlo A
authors.initials: GA
authors.lastname: Biagini
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Bray
authors.forename: Peter
authors.initials: P
authors.lastname: Gibbons
authors.forename: Neil
authors.initials: N
authors.lastname: Berry
authors.forename: Peter A
authors.initials: PA
authors.lastname: Winstanley
authors.forename: Amira
authors.initials: A
authors.lastname: Mukhtar
authors.forename: Richard
authors.initials: R
authors.lastname: Bonar-Law
authors.forename: Stephen
authors.initials: S
authors.lastname: Hindley
authors.forename: Ramesh B
authors.initials: RB
authors.lastname: Bambal
authors.forename: Charles B
authors.initials: CB
authors.lastname: Davis
authors.forename: Martin
authors.initials: M
authors.lastname: Bates
authors.forename: Timothy K
authors.initials: TK
authors.lastname: Hart
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Gresham
authors.forename: Ron M
authors.initials: RM
authors.lastname: Lawrence
authors.forename: Richard A
authors.initials: RA
authors.lastname: Brigandi
authors.forename: Federico M
authors.initials: FM
authors.lastname: Gomez-delas-Heras
authors.forename: Domingo V
authors.initials: DV
authors.lastname: Gargallo
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Ward
mesh_terms: D000634:Aminoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D000655:Amodiaquine / Q000031:analogs & derivatives; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D001596:Benzylamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D065607:Cytochrome P-450 Enzyme Inhibitors; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D004351:Drug Resistance; D005260:Female; D000882:Haplorhini; D006418:Heme / Q000737:chemistry; D006801:Humans; D008288:Malaria / Q000188:drug therapy; D051379:Mice; D008958:Models, Molecular; D010962:Plasmodium berghei / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects; D010967:Plasmodium yoelii; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000634:Aminoquinolines; D000962:Antimalarials; D001596:Benzylamines; D065607:Cytochrome P-450 Enzyme Inhibitors; C540176:N-tert-butylisoquine; D000655:Amodiaquine; D006418:Heme