Imidazolopiperazines: Lead Optimization of the Second-Generation Antimalarial Agents
| Autor: | Xuena Lin, Kelli Kuhen, Tao Wu, Elizabeth A. Winzeler, Christoph Fischli, Chun Li, Kerstin Gagaring, Jared Ek, Tiffany Chuan, Suresh B. Lakshminarayana, Rachel Borboa, Thomas Hollenbeck, Arnab K. Chatterjee, Fenghua Liu, Thierry T. Diagana, Richard Glynne, Caroline Francek, Reto Brun, Advait Nagle, John Isbell, Bo Liu, Christopher Caldwell, David C. Tully, David Plouffe, Tove Tuntland, Philip B. Alper, Suzanne Skolnik, Jonathan Chang, Jianling Wang, Matthias Rottmann, Zhong Chen |
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| Rok vydání: | 2012 |
| Předmět: |
Plasmodium falciparum
Biological Availability Pharmacology Article Piperazines Antimalarials Mice Structure-Activity Relationship chemistry.chemical_compound Pharmacokinetics In vivo Drug Discovery Animals Humans Structure–activity relationship Potency Antimalarial Agent Malaria Falciparum Rats Wistar Mice Inbred BALB C biology Imidazoles biology.organism_classification In vitro Rats Piperazine chemistry Molecular Medicine Caco-2 Cells |
| Zdroj: | Journal of Medicinal Chemistry |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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