Loading…

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 pharmac...

Full description

Saved in:
Bibliographic Details
Published in:Journal of medicinal chemistry 2009-03, Vol.52 (5), p.1408-1415
Main Authors: O’Neill, Paul M, Park, B. Kevin, Shone, Alison E, Maggs, James L, Roberts, Phillip, Stocks, Paul A, Biagini, Giancarlo A, Bray, Patrick G, Gibbons, Peter, Berry, Neil, Winstanley, Peter A, Mukhtar, Amira, Bonar-Law, Richard, Hindley, Stephen, Bambal, Ramesh B, Davis, Charles B, Bates, Martin, Hart, Timothy K, Gresham, Stephanie L, Lawrence, Ron M, Brigandi, Richard A, Gomez-delas-Heras, Federico M, Gargallo, Domingo V, Ward, Stephen A
Format: Article
Language:English
Subjects:
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm8012618