Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 52, Issue 5, Pages 1408-1415Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm8012618
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Funding
- Glaxo-Smithkline (GSK)
- Engineering and Physical Sciences Research Council (EPSRC)
- KEMRI-Wellcorne Trust Research
- Medical Research Council [G0700654B] Funding Source: researchfish
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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.
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