(2s-3as-7as)-1-(((r-r)-2-phenylcyclopropyl)carbonyl)-2-((thiazolidin-3-yl)carbonyl)octahydro-1h-indole and Cognition-Disorders

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.

Topics: Aging; Animals; Cognition Disorders; Humans; Indoles; Learning; Memory Disorders; Models, Animal; Prolyl Oligopeptidases; Serine Endopeptidases; Serine Proteinase Inhibitors; Substance P; Thiazoles; Thiazolidines

A number of neuropeptides are affected in Parkinson's disease and the enzyme proline endopeptidase contributes to the degradation of many of these neuropeptides, some of which are linked to a variety of cognitive functions. In the present study, the effects of the highly potent proline endopeptidase inhibitor S 17092 on cognitive deficits in monkeys induced by chronic low dose 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration were examined. Chronic low dose MPTP administration resulted in deficits in performance of variable delayed response, delayed matching-to-sample, and delayed alternation tasks. Seven day oral administration of S 17092 followed by single dose administration of the same dose on the day of testing significantly improved overall performance on these tasks. The most effective dose of S 17092 was 3 mg/kg. These results indicate that S 17092 has cognition-enhancing properties in this model of early parkinsonism.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Cognition Disorders; Conditioning, Operant; Discrimination Learning; Dopamine Agents; Indoles; Macaca fascicularis; Male; Parkinson Disease, Secondary; Pattern Recognition, Visual; Prolyl Oligopeptidases; Psychomotor Performance; Serine Endopeptidases; Serine Proteinase Inhibitors; Thiazoles; Thiazolidines