Imidazolopiperazines: Lead Optimization of the Second-Generation Antimalarial Agents
| العنوان: | Imidazolopiperazines: Lead Optimization of the Second-Generation Antimalarial Agents |
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| المؤلفون: | 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 |
| المصدر: | Journal of Medicinal Chemistry |
| بيانات النشر: | American Chemical Society (ACS), 2012. |
| سنة النشر: | 2012 |
| مصطلحات موضوعية: | 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 |
| الوصف: | 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. |
| تدمد: | 1520-4804 0022-2623 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f67dd0822748c0b26acd0f3ad90e7ef8 https://doi.org/10.1021/jm300041e |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....f67dd0822748c0b26acd0f3ad90e7ef8 |
| قاعدة البيانات: | OpenAIRE |
Find this issue from the American Chemical Society | تدمد: | 15204804 00222623 |
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