The Effect of Cyanopyrrolidine Derivatives on the Activity of Prolyl Endopeptidase, Acute Exudative Inflammation and Visceral Pain in Mice

Cyanopyrrolidine derivatives benzyloxycarbonyl-methionyl-cyanopyrrolidine (ZMetPrdN), benzyloxycarbonyl-phenylalanyl-cyanopyrrolidine (ZPhePrdN), tert-butyl-hydroxycarbonyl-glycyl-cyanopyrrolidine (BocGlyPrdN), tert-butyl-hydroxycarbonyl-methionyl-cyanopyrrolidine (BocMetPrdN) are inhibitors of prolyl endopeptidase (PREP; EC 3.4.21.26) with the IC50 values ranged from 2 nM to 12 nM. Besides inhibition of PREP, ZMetPrdN, ZPhePrdN, and BocMetPrdN also inhibited activity of dipeptidyl peptidase IV (DPP-4; EC 3.4.14.5) with the IC50 values ranged from 1100 nM to 3200 nM. In the acetic acid writhing test in mice all the compounds demonstrated antinociceptive properties. However, only the cyanopyrrolidine derivatives with aromatic substituents (ZMetPrdN and ZPhePrdN) decreased acute exudative inflammation in animals. Three hours after induction of inflammation, the studied cyanopyrrolidine derivatives increased PREP activity and compensatory decreased DPP-4 activity in serum of mice. Thus, one of the components of the mechanism responsible for realization of the antinociceptive and antiexudative properties of the studied derivatives of cyanopyrrolidine is obviously associated with their ability to inhibit PREP activity.