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

  • J Med Chem. 2023 Aug 10;66(15):10413-10431. doi: 10.1021/acs.jmedchem.3c00582.
Michael G Thomas  1 ,  Kate McGonagle  1 ,  Paul Rowland  2 ,  David A Robinson  1 ,  Peter G Dodd  1 ,  Isabel Camino-Díaz  3 ,  Lorna Campbell  1 ,  Juan Cantizani  4 ,  Pablo Castañeda  3 ,  Daniel Conn  2 ,  Peter D Craggs  2 ,  Darren Edwards  1 ,  Liam Ferguson  1 ,  Andrew Fosberry  2 ,  Laura Frame  1 ,  Panchali Goswami  2 ,  Xiao Hu  1 ,  Justyna Korczynska  2 ,  Lorna MacLean  1 ,  Julio Martin  4 ,  Nicole Mutter  1 ,  Maria Osuna-Cabello  1 ,  Christy Paterson  1 ,  Imanol Peña  4 ,  Erika G Pinto  1 ,  Caterina Pont  1 ,  Jennifer Riley  1 ,  Yoko Shishikura  1 ,  Frederick R C Simeons  1 ,  Laste Stojanovski  1 ,  John Thomas  1 ,  Karolina Wrobel  1 ,  Robert J Young  5 ,  Filip Zmuda  1 ,  Fabio Zuccotto  1 ,  Kevin D Read  1 ,  Ian H Gilbert  1 ,  Maria Marco  4 ,  Timothy J Miles  4 ,  Pilar Manzano  4 ,  Manu De Rycker  1
Affiliations
  • 1. Drug Discovery Unit, University of Dundee, School of Life Sciences, Dow Street, Dundee, U.K., DD1 5EH.
  • 2. GlaxoSmithKline, Chemistry, Medicines Research Centre, Gunnels Wood Road, Stevenage, U.K., SG1 2NY.
  • 3. GlaxoSmithKline, Discovery DMPK, IVIVT, Severo Ochoa 2, PTM, Tres Cantos, Madrid ES 28760, Spain.
  • 4. GlaxoSmithKline, Global Health R&D, Severo Ochoa 2, PTM, Tres Cantos, Madrid ES 28760, Spain.
  • 5. Blue Burgundy Ltd, Ampthill, Bedfordshire, U.K., MK45 2AD.
PMID: 37506194 DOI: 10.1021/acs.jmedchem.3c00582
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 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.

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