Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
J Med Chem. 2011 Jul 28;54(14):5116-30. doi: 10.1021/jm2003359. Epub 2011 Jun 23.
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.
从 GNF 化合物库系列中的一个热门化合物出发，基于对恶性疟原虫的基于细胞的增殖测定，优化了一种新型咪唑并哌嗪骨架。讨论了该系列化合物的 SAR，重点是针对野生型和耐药寄生虫的细胞效力的优化以及改善理化和药代动力学性质。该系列中的先导化合物在体外具有良好的活性，在体内具有良好的口服暴露水平。在伯氏疟原虫感染小鼠模型中，一种先导化合物在给予 100mg/kg 单剂量口服后，寄生虫血症水平降低了 99.4%，并使小鼠的平均存活时间延长了 17.0 天。这些先导化合物在初步的体外毒性研究中也具有良好的耐受性，是药物开发的一个有趣的先导化合物。
