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TitleStructure-Guided Design and Synthesis of a Pyridazinone Series of Proteasome Inhibitors.
Journal, issue, pagesJ Med Chem, Vol. 66, Issue 15, Page 10413-10431, Year 2023
Publish dateAug 10, 2023
AuthorsMichael 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 / Erika 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 /
PubMed AbstractThere 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, ...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 proteasome. A related analogue, active against , 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 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.
External linksJ Med Chem / PubMed:37506194 / PubMed Central
MethodsEM (single particle)
Resolution2.59 Å
Structure data

16963

8olu

EMDB-16963, PDB-8olu:
Leishmania tarentolae proteasome 20S subunit in complex with 1-Benzyl-N-(3-(cyclopropylcarbamoyl)phenyl)-6-oxo-1,6-dihydropyridazine-3-carboxamide
Method: EM (single particle) / Resolution: 2.59 Å

Chemicals

ChemComp-VYW:
~{N}-[3-(cyclopropylcarbamoyl)phenyl]-6-oxidanylidene-1-(phenylmethyl)pyridazine-3-carboxamide

Source
  • leishmania tarentolae (eukaryote)
KeywordsUNKNOWN FUNCTION / Proteasome 20S subunit

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