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.