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

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.
Paul M O'Neill 1,  B Kevin Park,  Alison E Shone,  James L Maggs,  Phillip Roberts,  Paul A Stocks,  Giancarlo A Biagini,  Patrick G Bray,  Peter Gibbons,  Neil Berry,  Peter A Winstanley,  Amira Mukhtar,  Richard Bonar-Law,  Stephen Hindley,  Ramesh B Bambal,  Charles B Davis,  Martin Bates,  Timothy K Hart,  Stephanie L Gresham,  Ron M Lawrence,  Richard A Brigandi,  Federico M Gomez-delas-Heras,  Domingo V Gargallo,  Stephen A Ward
Affiliations

Affiliation

  • 1 Department of Chemistry, University of Liverpool, Liverpool, United Kingdom. p.m.oneill01@liv.ac.uk
PMID: 19222165 DOI: 10.1021/jm8012618
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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z