S 17092: a prolyl endopeptidase inhibitor as a potential therapeutic drug for memory impairment. Preclinical and clinical studies.
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)carbonyl]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.
Morain
Philippe
P
Institut de Recherches Internationales Servier, 6 Place des pleïades, 92415 Courbevoie, France. philippe.morain@fr.netgrs.com.
Lestage
Pierre
P
De Nanteuil
Guillaume
G
Jochemsen
Roeline
R
Robin
Jean-Loïc
JL
Guez
David
D
Boyer
Pierre-Alain
PA
D000375:Aging; D000818:Animals; D003072:Cognition Disorders / Q000139:chemically induced / Q000188:drug therapy*; D006801:Humans; D007211:Indoles / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D007858:Learning / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced / Q000188:drug therapy*; D023421:Models, Animal; D000085822:Prolyl Oligopeptidases; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D013373:Substance P / Q000378:metabolism; D013844:Thiazoles / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D053778:Thiazolidines
D007211:Indoles; C118986:S 17092-1; D015842:Serine Proteinase Inhibitors; D013844:Thiazoles; D053778:Thiazolidines; D013373:Substance P; D012697:Serine Endopeptidases; C000705287:PREPL protein, human; D000085822:Prolyl Oligopeptidases