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

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.