Candidate selection and preclinical evaluation of N-tert-butyl isoquine (GSK369796), an affordable and effective 4-aminoquinoline antimalarial for the 21st century.
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.
O'Neill
Paul M
PM
Department of Chemistry, University of Liverpool, Liverpool, United Kingdom. p.m.oneill01@liv.ac.uk
Park
B Kevin
BK
Shone
Alison E
AE
Maggs
James L
JL
Roberts
Phillip
P
Stocks
Paul A
PA
Biagini
Giancarlo A
GA
Bray
Patrick G
PG
Gibbons
Peter
P
Berry
Neil
N
Winstanley
Peter A
PA
Mukhtar
Amira
A
Bonar-Law
Richard
R
Hindley
Stephen
S
Bambal
Ramesh B
RB
Davis
Charles B
CB
Bates
Martin
M
Hart
Timothy K
TK
Gresham
Stephanie L
SL
Lawrence
Ron M
RM
Brigandi
Richard A
RA
Gomez-delas-Heras
Federico M
FM
Gargallo
Domingo V
DV
Ward
Stephen A
SA
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
D000634:Aminoquinolines; D000962:Antimalarials; D001596:Benzylamines; D065607:Cytochrome P-450 Enzyme Inhibitors; C540176:N-tert-butylisoquine; D000655:Amodiaquine; D006418:Heme