Discovery of aminoheterocycles as potent and brain penetrant prolylcarboxypeptidase inhibitors.

Abstract Efforts were dedicated to develop potent and brain penetrant prolylcarboxypeptidase (PrCP) inhibitors by replacing the amide group of original leads 1 and 2 with heterocycles. Aminopyrimidines including compound 32a were identified to display good PrCP inhibitory activity ( 32a , IC 50  = 43 nM) and impressive ability to penetrate brain in mice (brain/plasma ratio: 1.4).