Synthesis and evaluation of succinic acid derivatives as prolyl endopeptidase inhibitors

Abstract

Many synthetic peptide-based prolyl endopeptidase (PEP) inhibitors are depended on the acy-l-L-prolyl-pyrrolidine structure. The pyrrolidine ring at P1 and a large variety of lipophilic acyl groups at P3 have been reported to be important for potent PEP inhibitory activity. Upon exploration of a new lead compound for PEP inhibition, succinic acid was introduced at the P2 position to replace the l-proline in acyl-l-prolyl-pyrrolidine. A series of amido-succinylpyrrolidine compounds (1–9) were synthesized, and their PEP inhibitory activities were evaluated. Of these, compound 9 showed the most potent PEP inhibitory activity with IC50 of 6.4±0.6 nM.