Candidate Selection and Preclinical Evaluation of N-tert-Butyl Isoquine (GSK369796), An Affordable and Effective 4-Aminoquinoline Antimalarial for the 21st Century

• Published in: Journal of medicinal chemistry Vol. 52; no. 5; pp. 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: Journal Article
• Language: English
• Published: Columbus, OH American Chemical Society 12.03.2009
• Subjects: Aminoquinolines - chemical synthesis; Aminoquinolines - chemistry; Aminoquinolines - pharmacokinetics; Aminoquinolines - pharmacology; Aminoquinolines - toxicity; Amodiaquine - analogs & derivatives; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antimalarials - chemical synthesis; Antimalarials - pharmacokinetics; Antimalarials - pharmacology; Antimalarials - toxicity; Antiparasitic agents; Benzylamines - chemical synthesis; Benzylamines - chemistry; Benzylamines - pharmacology; Benzylamines - toxicity; Biological and medical sciences; Cytochrome P-450 Enzyme Inhibitors; Dogs; Drug Evaluation, Preclinical; Drug Resistance; Female; Haplorhini; Heme - chemistry; Humans; Malaria - drug therapy; Medical sciences; Mice; Models, Molecular; Pharmacology. Drug treatments; Plasmodium berghei - drug effects; Plasmodium falciparum - drug effects; Plasmodium yoelii; Rats; Structure-Activity Relationship; Antimalarial; Protozoal disease; Plasmodium yoelii; Aminophenols; Antiprotozoal agent; Plasmodium falciparum; Plasmodium berghei; Chlorine Organic compounds; Secondary amine; Protozoa; Apicomplexa; Malaria; Rodentia; Oral administration; Quinoline derivatives; Parasitosis; In vitro; Biological activity; Infection; In vivo; Vertebrata; Chemotherapy; Mammalia; Treatment; Mouse; Animal; Parasiticide; Pharmacokinetics
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm8012618

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.