Structure-Guided Design and Synthesis of a Pyridazinone Series of Trypanosoma cruzi 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 Korczynska , Lorna MacLean, Julio Martin , Nicole Mutter , Maria Osuna-Cabello , Christy Paterson , Imanol Peña , Er ika 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 , Maria Marco , Timothy J Miles, Pilar Manzano , Manu De Rycker.

J Med Chem. 2023 Jul 28. doi: 10.1021/acs.jmedchem.3c00582. Epub ahead of print. PMID: 37506194.


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