Thomas Michael G, Dunne Joanne, Dodd Peter G, D'Oria Emiliana, Frame Laura, Garcia-Perez Adolfo, McGonagle Kate, Manzano Pilar, MacLean Lorna, Paterson Christy, Riley Jennifer, Thomas John, Torrie Leah S, Wrobel Karolina, Read Kevin D, Marco Maria, De Rycker Manu
Drug Discovery Unit, University of Dundee Dundee UK
Tres Cantos Medicines Development Campus, DDW and CIB, GlaxoSmithKline Tres Cantos Spain.
RSC Med Chem. 2025 Jun 6. doi: 10.1039/d5md00185d.
Chagas disease, caused by infection with the protozoan parasite (), is responsible for a large health burden with around 6-8 million people infected globally. The current drug development pipeline is sparsely populated and there is an urgent need for new treatments. In this paper we describe the identification of a series of benzodiazepinediones with antiparasitic activity, and the platform we utilised to demonstrate that they act a novel mechanism of action. Two distinct sub-series were identified, and the medicinal chemistry program identified compounds from both with pIC's >6.4 which were progressed to a washout assay. This assay showed that neither sub-series was suitable for further development. This work demonstrated the value of a robust Chagas disease discovery platform for focusing the limited resources available for neglected disease drug discovery onto the most promising series.
恰加斯病由原生动物寄生虫（）感染引起，在全球造成约600 - 800万人感染，带来了沉重的健康负担。目前的药物研发渠道药物稀少，迫切需要新的治疗方法。在本文中，我们描述了一系列具有抗寄生虫活性的苯并二氮杂䓬二酮的鉴定，以及我们用于证明它们通过一种新作用机制发挥作用的平台。鉴定出了两个不同的子系列，药物化学项目从这两个子系列中鉴定出pIC值>6.4的化合物，并将其推进到洗脱试验。该试验表明，这两个子系列都不适合进一步开发。这项工作证明了一个强大的恰加斯病发现平台的价值，该平台可将用于被忽视疾病药物发现的有限资源集中在最有前景的系列上。
