Imidazolopiperazines: Hit to Lead Optimization of New Antimalarial Agents

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• 作者：Tao Wu ; Advait Nagle ; Kelli Kuhen ; Kerstin Gagaring ; Rachel Borboa ; Caroline Francek ; Zhong Chen ; David Plouffe ; Anne Goh ; Suresh B. Lakshminarayana ; Jeanette Wu ; Hui Qing Ang ; Peiting Zeng ; Min Low Kang ; William Tan ; Maria Tan ; Nicole Ye ; Xuena Lin ; Christopher Caldwell ; Jared Ek ; Suzanne Skolnik ; Fenghua Liu ; Jianling Wang ; Jonathan Chang ; Chun Li ; Thomas Hollenbeck ; Tove Tuntland ; John Isbell ; Christoph Fischli ; Reto Brun ; Matthias Rottmann ; Veronique Dartois ; Thomas Keller ; Thierry Diagana ; Elizabeth Winzeler ; Richard Glynne ; David C. Tully ; Arnab K. Chatterjee
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：July 28, 2011
• 年：2011
• 卷：54
• 期：14
• 页码：5116-5130
• 全文大小：1170K
• 年卷期：v.54,no.14(July 28, 2011)
• ISSN：1520-4804

文摘

Starting from a hit series from a GNF compound library collection and based on a cell-based proliferation assay of Plasmodium falciparum, a novel imidazolopiperazine scaffold was optimized. SAR for this series of compounds is discussed, focusing on optimization of cellular potency against wild-type and drug resistant parasites and improvement of physiochemical and pharmacokinetic properties. The lead compounds in this series showed good potencies in vitro and decent oral exposure levels in vivo. In a Plasmodium berghei mouse infection model, one lead compound lowered the parasitemia level by 99.4% after administration of 100 mg/kg single oral dose and prolonged mice survival by an average of 17.0 days. The lead compounds were also well-tolerated in the preliminary in vitro toxicity studies and represents an interesting lead for drug development.