Structure-Guided Design and Synthesis of a Pyridazinone Series of Trypanosoma cruzi Proteasome Inhibitors

There is an urgentneed for new treatments for Chagasdisease,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 throughinhibition of the Leishmania proteasome. A relatedanalogue, active against Trypanosoma cruzi, showed suboptimal efficacy in an animal model of Chagas disease,so alternative proteasome inhibitors were investigated. Screeninga library of phenotypically active analogues against the T. cruzi proteasome identified an active, selectivepyridazinone, the development of which is described herein. We obtaineda cryo-EM co-structure of proteasome and a key inhibitor and usedthis to drive optimization of the compounds. Alongside this, optimizationof 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 plansto further understand the series and its potential to deliver a newtreatment for Chagas disease.