JTP-4819: a novel prolyl endopeptidase inhibitor with potential as a cognitive enhancer

JTP-4819 ((S)-2-[[(S)-2-(hydroxyacetyl)-1-pyrrolidinyl]carbonyl]-N- phenylmethyl)-1-pyrrolidinecarboxamide) is a potent (IC50: 0.83 +/- 0.09 nM in rat brain supernatant; 5.43 +/- 0.81 nM in Flavobacterium meningosepticum) and specific inhibitor of prolyl endopeptidase (PEP). JTP-4819 (3 mg/kg p.o.) exhibited a strong and durable ex vivo inhibitory effect on PEP in various regions of the rat brain. In addition, JTP-4819 inhibited the degradation of substance P, arginine-vasopressin, thyrotropin-releasing hormone, neurotensin, oxytocin, bradykinin, and angiotensin II by purified PEP with IC50 values of 9.6, 13.9, 10.7, 14.0, 4.5, 7.6 and 10.6 nM, respectively. In the one-trial passive avoidance test in rats with scopolamine-induced amnesia, JTP-4819 significantly prolonged the retention time when administered orally at doses of 1 and 3 mg/kg 1 hr before acquisition or at 3 and 10 mg/kg 1 hr before retention. In addition, coadministration of JTP-4819 and substance P, arginine-vasopressin or thyrotropin-releasing hormone (at doses at which each drug alone did not prolong the retention time) improved the retention time of rats with scopolamine-induced amnesia. Microdialysis studies demonstrated that JTP-4819 caused a significant increase in ACh release in the frontal cortex and hippocampus of young rats at oral doses of 1 and 3 mg/kg, as well as in both brain regions of aged rats at a dose of 3 mg/kg. These results indicate that JTP-4819 potentiates neuropeptide functions inhibiting PEP, that it activates cholinergic transmission and that it enhances learning and memory.