Structure-activity relationship study of novel tissue transglutaminase inhibitors.
Thieno[2,3-d]pyrimidin-4-one acylhydrazide derivatives were discovered as moderately potent inhibitors of TGase 2 (tissue transglutaminase) utilizing a fluorescence-based assay that measured TGase 2 catalyzed incorporation of the dansylated Lys derivative alpha-N-Boc-Lys-CH(2)-CH(2)-dansyl into the protein substrate N,N-dimethylated-casein. A SAR study revealed that the acylhydrazide thioether side-chain and the thiophene ring were critical to inhibitory activity.
Duval
Eric
E
Laboratory for Drug Discovery in Neurodegeneration, Harvard Center for Neurodegeneration and Repair, Brigham & Women's Hospital and Harvard Medical School, 65 Landsdowne Street, Cambridge, MA 02139, USA.
Case
April
A
Stein
Ross L
RL
Cuny
Gregory D
GD
D001665:Binding Sites; D002364:Caseins / Q000494:pharmacology; D002384:Catalysis; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006834:Hydrazines / Q000138:chemical synthesis* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D010455:Peptides / Q000737:chemistry; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013440:Sulfides / Q000737:chemistry*; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D011503:Transglutaminases / Q000037:antagonists & inhibitors*
D002364:Caseins; D004791:Enzyme Inhibitors; D006834:Hydrazines; D010455:Peptides; D013440:Sulfides; D013876:Thiophenes; C502583:thieno(2,3-d)pyrimidin-4-one acylhydrazide; D011503:Transglutaminases