Small molecule inhibitors of the p53-MDM2 protein complex are under intense investigation in clinical trials as anti-cancer agents, including our first generation inhibitor NVP-CGM097. We recently described the rational design of a novel pyrazolopyrrolidinone core as a new lead structure and now we report on the synthesis and optimization of this to provide a highly potent lead compound. This new compound displayed excellent oral efficacy in our preclinical mechanistic in vivo model and marked a significant milestone towards the identification of our second generation clinical candidate NVP-HDM201.

中文翻译：

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新型高效p53-MDM2抑制剂的体外和体内表征

p53-MDM2蛋白复合物的小分子抑制剂正在作为抗癌剂进行临床试验，包括我们的第一代抑制剂NVP-CGM097。我们最近描述了一种新颖的吡唑并吡咯烷酮核心作为新的先导结构的合理设计，现在我们就其合成和优化进行了报道，以提供一种高效的先导化合物。这种新化合物在我们的临床前机制体内模型中显示出优异的口服功效，并为鉴定我们的第二代临床候选药物NVP-HDM201奠定了重要的里程碑。