15 research outputs found
Scaffold-Hopping Strategy on a Series of Proteasome Inhibitors Led to a Preclinical Candidate for the Treatment of Visceral Leishmaniasis
Identification and development of a series of disubstituted piperazines for the treatment of Chagas disease
2-Acetylpyridinium bromanilate
In the crystal of the title molecular salt (systematic name: 2-acetylpyridinium 2,5-dibromo-4-hydroxy-3,6-dioxocyclohexa-1,4-dienolate), C7H8NO+·C6HBr2O4
−, centrosymmetric rings consisting of two cations and two anions are formed, with the components linked by alternating O—H⋯O and N—H⋯O hydrogen bonds. Short O⋯Br contacts [3.243 (2) and 3.359 (2) Å] may help to consolidate the packing
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.</p
Cell-active Small Molecule Inhibitors of the DNA-damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG) : Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides
DNA
damage repair enzymes are promising targets in the development
of new therapeutic agents for a wide range of cancers and potentially
other diseases. The enzyme poly(ADP-ribose) glycohydrolase (PARG)
plays a pivotal role in the regulation of DNA repair mechanisms; however,
the lack of potent drug-like inhibitors for use in cellular and in
vivo models has limited the investigation of its potential as a novel
therapeutic target. Using the crystal structure of human PARG in complex
with the weakly active and cytotoxic anthraquinone <b>8a</b>, novel quinazolinedione sulfonamides PARG inhibitors have been identified
by means of structure-based virtual screening and library design.
1-Oxetan-3-ylmethyl derivatives <b>33d</b> and <b>35d</b> were selected for preliminary investigations in vivo. X-ray crystal
structures help rationalize the observed structure–activity
relationships of these novel inhibitors