Imidazolopiperazines: lead optimization of the second-generation antimalarial agents

Nagle, A. and Wu, T. and Kuhen, K. and Gagaring, K. and Borboa, R. and Francek, C. and Chen, Z. and Plouffe, D. and Lin, X. and Caldwell, C. and Ek, J. and Skolnik, S. and Liu, F. and Wang, J. and Chang, J. and Li, C. and Liu, B. and Hollenbeck, T. and Tuntland, T. and Isbell, J. and Chuan, T. and Alper, P. B. and Fischli, C. and Brun, R. and Lakshminarayana, S. B. and Rottmann, M. and Diagana, T. T. and Winzeler, E. A. and Glynne, R. and Tully, D. C. and Chatterjee, A. K.. (2012) Imidazolopiperazines: lead optimization of the second-generation antimalarial agents. Journal of medicinal chemistry, 55 (9). pp. 4244-4273.

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Official URL: http://edoc.unibas.ch/dok/A6094222

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On the basis of the initial success of optimization of a novel series of imidazolopiperazines, a second generation of compounds involving changes in the core piperazine ring was synthesized to improve antimalarial properties. These changes were carried out to further improve the potency and metabolic stability of the compounds by leveraging the outcome of a set of in vitro metabolic identification studies. The optimized 8,8-dimethyl imidazolopiperazine analogues exhibited improved potency, in vitro metabolic stability profile and, as a result, enhanced oral exposure in vivo in mice. The optimized compounds were found to be more efficacious than the current antimalarials in a malaria mouse model. They exhibit moderate oral exposure in rat pharmacokinetic studies to achieve sufficient multiples of the oral exposure at the efficacious dose in toxicology studies
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology (MPI) > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Brun, Reto and Rottmann, Matthias
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Chemical Society
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:13 Sep 2018 14:29
Deposited On:19 Jul 2013 07:38

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