Pyrimido[5,4-e][1,2,4]triazine-5,7(1H,6H)-dione derivatives as novel small molecule chaperone amplifiers

• Published in: Bioorganic & medicinal chemistry letters 2009-08, Vol.19 (15), p.4303-4307
• Main Authors: Zhou, Yuefen, Wei, Linyi, Brady, Thomas P., Murali Mohan Redddy, P.S., Nguyen, Tram, Chen, Jinhua, Au, Qingyan, Yoon, Il Sang, Yip, Gary, Zhang, Bin, Barber, Jack R., Ng, Shi Chung
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Cell Line, Tumor; Chemistry, Pharmaceutical - methods; Cytoprotection; DNA-Binding Proteins - chemistry; Drug Design; Glucose - chemistry; Heat shock proteins (HSPs); Heat Shock Transcription Factors; HSF1; Humans; Medical sciences; Models, Chemical; Molecular Chaperones - chemistry; Neurodegenerative diseases; Neurodegenerative Diseases - drug therapy; Neuropharmacology; Neuroprotective agent; OGD; Oxygen - chemistry; Pharmacology. Drug treatments; Protein Conformation; Protein Folding; Protein misfolding; Pyrimidinones - chemical synthesis; Pyrimidotriazinedione derivatives; Rats; Rotenone - chemical synthesis; Rotenone - pharmacology; Rotenone stress; Small molecule chaperone amplifiers; Stress granule; Structure-Activity Relationship; Transcription Factors - chemistry; Triazines - chemistry; Triazines - pharmacology; Uracil - analogs & derivatives; Uracil - chemistry; Uracil - pharmacology
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.05.073

Pyrimido[5,4-e][1,2,4]triazine-5,7(1H,6H)-dione derivatives were investigated as novel small molecule amplifiers of heat shock factor 1 transcriptional activity. Lead optimization led to the discovery of compound 4A-13, which displayed potent HSF1 activity under mild heat stress (EC50=2.5μM) and significant cytoprotection in both rotenone (EC50=0.23μM) and oxygen-glucose deprivation cell toxicity models (80% protection at 2.5μM).