Candidate selection and preclinical evaluation of N-tert-butyl isoquine (GSK369796), an affordable and effective 4-aminoquinoline antimalarial for the 21st century.

Article Details

Citation

O'Neill PM, Park BK, Shone AE, Maggs JL, Roberts P, Stocks PA, Biagini GA, Bray PG, Gibbons P, Berry N, Winstanley PA, Mukhtar A, Bonar-Law R, Hindley S, Bambal RB, Davis CB, Bates M, Hart TK, Gresham SL, Lawrence RM, Brigandi RA, Gomez-delas-Heras FM, Gargallo DV, Ward SA

Candidate selection and preclinical evaluation of N-tert-butyl isoquine (GSK369796), an affordable and effective 4-aminoquinoline antimalarial for the 21st century.

J Med Chem. 2009 Mar 12;52(5):1408-15. doi: 10.1021/jm8012618.

PubMed ID
19222165 [ View in PubMed
]
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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
AmodiaquineCytochrome P450 2C9IC 50 (nM)62000N/AN/ADetails
AmodiaquineCytochrome P450 2D6IC 50 (nM)6100N/AN/ADetails
HalofantrinePotassium voltage-gated channel subfamily H member 2IC 50 (nM)40N/AN/ADetails