Structure-Guided Design and Synthesis of a Pyridazinone Series of <i>Trypanosoma cruzi</i> Proteasome Inhibitors
Michael G. Thomas, Kate McGonagle, Paul Rowland, David A. Robinson, Peter G. Dodd, Isabel Camino-Díaz, Lorna Campbell, Juan Cantizani, Pablo Castañeda, Daniel Conn, Peter D. Craggs, Darren Edwards, Liam Ferguson, Andrew Fosberry, Laura Frame, Panchali Goswami, Xiao Hu, Justyna Korczyńska, Lorna MacLean, Julio Martín, Nicole Mutter, Maria Osuna‐Cabello, Christy Paterson, Imanol Peña, Érika G. Pinto, Caterina Pont, Jennifer Riley, Yoko Shishikura, Frederick R. C. Simeons, Laste Stojanovski, John Thomas, Karolina Wrobel, Robert J. Young, Filip Zmuda, Fabio Zuccotto, Kevin D. Read, Ian H. Gilbert, María Marco, Timothy J. Miles, Pilar Manzano, Manu De Rycker
Abstract
High Resolution Image Download MS PowerPoint Slide 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 Leishmania proteasome. 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. cruzi proteasome 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.