Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, University of Dundee, Dundee, DD1 5EH, UK.
Global Health R&D, GlaxoSmithKline, Tres Cantos, 28760, Spain.
Eur J Med Chem. 2022 Aug 5;238:114421. doi: 10.1016/j.ejmech.2022.114421. Epub 2022 May 6.
Approximately 6-7 million people around the world are estimated to be infected with Trypanosoma cruzi, the causative agent of Chagas disease. The current treatments are inadequate and therefore new medical interventions are urgently needed. In this paper we describe the identification of a series of disubstituted piperazines which shows good potency against the target parasite but is hampered by poor metabolic stability. We outline the strategies used to mitigate this issue such as lowering logD, bioisosteric replacements of the metabolically labile piperazine ring and use of plate-based arrays for quick diversity scoping. We discuss the success of these strategies within the context of this series and highlight the challenges faced in phenotypic programs when attempting to improve the pharmacokinetic profile of compounds whilst maintaining potency against the desired target.
据估计，全球约有 600 万至 700 万人感染克氏锥虫，这种寄生虫是恰加斯病的病原体。目前的治疗方法并不完善，因此迫切需要新的医疗干预措施。在本文中，我们描述了一系列二取代哌嗪的鉴定，这些哌嗪对靶寄生虫具有良好的活性，但代谢稳定性差。我们概述了用于减轻此问题的策略，例如降低 logD、代谢不稳定的哌嗪环的生物等排体替换以及使用基于平板的阵列进行快速多样性评估。我们讨论了这些策略在该系列中的成功，并强调了在尝试改善化合物的药代动力学特性的同时保持对所需靶标的活性时，在表型项目中面临的挑战。
