학술논문
Structure-Guided Design and Synthesis of a Pyridazinone Series of Trypanosoma cruziProteasome Inhibitors
Document Type
Article
Author
Thomas, Michael G.; McGonagle, Kate; Rowland, Paul; Robinson, David A.; Dodd, Peter G.; Camino-Díaz, Isabel; Campbell, Lorna; Cantizani, Juan; Castañeda, Pablo; Conn, Daniel; Craggs, Peter D.; Edwards, Darren; Ferguson, Liam; Fosberry, Andrew; Frame, Laura; Goswami, Panchali; Hu, Xiao; Korczynska, Justyna; MacLean, Lorna; Martin, Julio; Mutter, Nicole; Osuna-Cabello, Maria; Paterson, Christy; Peña, Imanol; Pinto, Erika G.; Pont, Caterina; Riley, Jennifer; Shishikura, Yoko; Simeons, Frederick R. C.; Stojanovski, Laste; Thomas, John; Wrobel, Karolina; Young, Robert J.; Zmuda, Filip; Zuccotto, Fabio; Read, Kevin D.; Gilbert, Ian H.; Marco, Maria; Miles, Timothy J.; Manzano, Pilar; De Rycker, Manu
Source
Journal of Medicinal Chemistry; August 2023, Vol. 66 Issue: 15 p10413-10431, 19p
Subject
Language
ISSN
00222623; 15204804
Abstract
There is an urgent need for new treatments for Chagas disease, a parasitic infection which mostly impacts South and Central America. We previously reported on the discovery of GSK3494245/DDD01305143, a preclinical candidate for visceral leishmaniasis which acted through inhibition of the Leishmaniaproteasome. A related analogue, active against Trypanosoma cruzi, showed suboptimal efficacy in an animal model of Chagas disease, so alternative proteasome inhibitors were investigated. Screening a library of phenotypically active analogues against the T. cruziproteasome identified an active, selective pyridazinone, the development of which is described herein. We obtained a cryo-EM co-structure of proteasome and a key inhibitor and used this to drive optimization of the compounds. Alongside this, optimization of the absorption, distribution, metabolism, and excretion (ADME) properties afforded a suitable compound for mouse efficacy studies. The outcome of these studies is discussed, alongside future plans to further understand the series and its potential to deliver a new treatment for Chagas disease.