Open AccessS 17092: A Prolyl Endopeptidase Inhibitor as a Potential Therapeutic Drug for Memory Impairment. Preclinical and Clinical Studies
Author(s) -
Morain Philippe,
Lestage Pierre,
Nanteuil Guillaume,
Jochemsen Roeline,
Robin JeanLoïc,
Guez David,
Boyer PierreAlain
Publication year - 2002
Publication title -
cns drug reviews
Language(s) - English
Resource type - Journals
eISSN - 1527-3458
pISSN - 1080-563X
DOI - 10.1111/j.1527-3458.2002.tb00214.x
Subject(s) - prolyl endopeptidase , neprilysin , neuroscience , amnesia , memory impairment , pharmacology , neuropeptide , inhibitory postsynaptic potential , psychology , cognition , memory improvement , drug , medicine , chemistry , receptor , psychiatry , biochemistry , enzyme
Any treatment that could positively modulate central neuropeptides levels would provide a promising therapeutic approach to the treatment of cognitive deficits associated with aging and/or neurodegenerative diseases. Therefore, based on the activity in rodents, S 17092 (2S,3aS,7aS)‐1 ([(R.R)‐2‐phenylcyclopropyl]carbonyl)‐2‐[(thiazolidin‐3‐yl)car‐bonyl]octahydro‐ 1H ‐indole) has been selected as a potent inhibitor of cerebral prolyl‐endopeptidase (PEP). By retarding the degradation of neuroactive peptides, S 17092 was successfully used in a variety of memory tasks. These tasks explored short‐term, long‐term, reference and working memory in aged mice, as well as in rodents and monkeys with chemically induced amnesia or spontaneous memory deficits. S 17092 has also been safely administered to humans, and showed a clear peripheral expression of its mechanism of action through its inhibitory effect upon PEP activity in plasma. S 17092 exhibited central effects, as evidenced by EEG recording in healthy volunteers, and could improve a delayed verbal memory task. Collectively, the preclinical and clinical effects of S 17092 have suggested a promising role for this compound as an agent for the treatment of cognitive disorders associated with cerebral aging.