Imidazolopiperazines: Lead Optimization of the Second-Generation Antimalarial Agents

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• 作者：Advait Nagle ; Tao Wu ; Kelli Kuhen ; Kerstin Gagaring ; Rachel Borboa ; Caroline Francek ; Zhong Chen ; David Plouffe ; Xuena Lin ; Christopher Caldwell ; Jared Ek ; Suzanne Skolnik ; Fenghua Liu ; Jianling Wang ; Jonathan Chang ; Chun Li ; Bo Liu ; Thomas Hollenbeck ; Tove Tuntland ; John Isbell ; Tiffany Chuan ; Philip B. Alper ; Christoph Fischli ; Reto Brun ; Suresh B. Lakshminarayana ; Matthias Rottmann ; Thierry T. Diagana ; Elizabeth A. Winzeler ; Richard Glynne ; David C. Tully ; Arnab K. Chatterjee
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：May 10, 2012
• 年：2012
• 卷：55
• 期：9
• 页码：4244-4273
• 全文大小：1806K
• 年卷期：v.55,no.9(May 10, 2012)
• ISSN：1520-4804

文摘

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.