Inhibitors of type I MetAPs containing pyridine-2-carboxylic acid thiazol-2-ylamide. Part 1: SAR studies on the determination of the key scaffold.
Systematic SAR studies on the HTS hit pyridine-2-carboxylic acid thiazol-2-ylamide (PACT) analogues revealed that the scaffold of PCAT is indispensable for the inhibition of type I MetAP. For effective inhibition of the enzyme, the most suitable position to modify is the 3-position of the pyridine ring of PCAT, and the best substituents are those containing O or N atoms connected directly with the pyridine ring. These findings provide useful information for the design and discovery of more potent inhibitors of type I MetAPs.
Luo
Qun-Li
QL
Chinese National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 189 Guoshoujing Road, Zhangjiang Hi-Tech Park, Shanghai 201203, PR China.
Li
Jing-Ya
JY
Liu
Zhi-Ying
ZY
Chen
Ling-Ling
LL
Li
Jia
J
Ye
Qi-Zhuang
QZ
Nan
Fa-Jun
FJ
D000577:Amides / Q000737:chemistry* / Q000494:pharmacology; D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D000935:Antifungal Agents / Q000138:chemical synthesis / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors; D004926:Escherichia coli / Q000201:enzymology; D006801:Humans; D020128:Inhibitory Concentration 50; D063208:Methionyl Aminopeptidases; D011725:Pyridines / Q000138:chemical synthesis / Q000494:pharmacology; D012486:Salmonella typhimurium / Q000201:enzymology; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry* / Q000494:pharmacology; D013854:Thioamides / Q000138:chemical synthesis* / Q000494:pharmacology
D000577:Amides; D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D001426:Bacterial Proteins; D011725:Pyridines; D013844:Thiazoles; D013854:Thioamides; C500876:pyridine-2-carboxylic acid thiazol-2-ylamide; D000626:Aminopeptidases; D063208:Methionyl Aminopeptidases