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O'Neill, Paul M., Park, B. Kevin, Shone, Alison, Maggs, James L., Roberts, Phillip, Stocks, Paul A., Biagini, Giancarlo 
ORCID: https://orcid.org/0000-0001-6356-6595, Bray, Patrick, 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. and Ward, Stephen ORCID: https://orcid.org/0000-0003-2331-3192
(2009)
'Candidate Selection and Preclinical Evaluation of N-tert-Butyl Isoquine (GSK369796), An Affordable and Effective 4-Aminoquinoline Antimalarial for the 21st Century'. Journal of Medicinal Chemistry, Vol 52, Issue 5, pp. 1408-1415.
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.
| Item Type: | Article |
|---|---|
| Subjects: | QV Pharmacology > Drug Standardization. Pharmacognosy. Medicinal Plants > QV 771 Standardization and evaluation of drugs WC Communicable Diseases > Tropical and Parasitic Diseases > WC 750 Malaria QV Pharmacology > QV 4 General works QV Pharmacology > QV 38 Drug action. QX Parasitology > QX 20 Research (General) QX Parasitology > QX 4 General works QX Parasitology > Protozoa > QX 135 Plasmodia QX Parasitology > QX 45 Host-parasite relations QW Microbiology and Immunology > QW 45 Microbial drug resistance. General or not elsewhere classified. |
| Faculty: Department: | Groups (2002 - 2012) > Molecular & Biochemical Parasitology Group |
| Digital Object Identifer (DOI): | https://doi.org/10.1021/jm8012618 |
| Depositing User: | Mary Creegan |
| Date Deposited: | 18 Jun 2010 09:00 |
| Last Modified: | 17 Jul 2020 10:57 |
| URI: | https://archive.lstmed.ac.uk/id/eprint/356 |
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