S 17092: A Prolyl Endopeptidase Inhibitor as a Potential Therapeutic Drug for Memory Impairment. Preclinical and Clinical Studies

Abstract

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 prolylendopeptidase (PEP). By retarding the degradation of neuroactive peptides, S 17092 was successfully used in a variety of memory tasks. These tasks explored short-term, longterm, 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.

Decreased Endogenous Levels of Ac-SDKP Promote Organ Fibrosis

“…POPi was mixed with peanut oil and administered daily by gavage. 11 After 1 week rats were euthanized and the heart, kidneys, and brain were rapidly frozen in liquid nitrogen (LN 2 ) and kept at Ϫ70°C until processing. We used commercially available enzyme immunoassay kits to measure Ac-SDKP (Cayman Chemicals) as well as Arg 8 -vasopressin and substance-P (Assay Designs) and Ang II (Peninsula Laboratories).…”

Prolyl oligopeptidase attenuates hepatic stellate cell activation through induction of Smad7 and PPAR-γ

“…As a potent inhibitor of POP, S17092 has been considered as a promising therapeutic compound for memory impairment (40). In the present study, the effects of S17092 on HSC-T6 cells were investigated.…”

Peptidomics of the Prolyl Peptidases

“…The unique biochemical activity of Prep, namely the ability to cleave peptides at proline amino acids, has prompted a great deal of research into the biochemical, cellular, and physiological functions of this protein (9). In vitro assays have identified Prep substrates that range from the tripeptide, thyrotropin-releasing hormone, to a 31 amino acid peptide, beta endorphin (9,34), which led to new hypotheses about the physiological role of Prep, including a role in cognitive function (15)(16)(17)(18).…”

“…Differences in ion abundance between the two samples revealed Prep-regulated peptides, including substrates and products of the enzyme. c The identification of natural substrates, such as Hspa12a (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23), revealed that Prep can show cleavage site selectivity between two proline amino acids, which would not have been predicted based on the known substrate selectivity of Prep. d Prep also showed a length dependence, preferring shorter substrates, which allows it to cleave the degradation fragment of CGRP, CGRP(20-37), without cleaving the bioactive species CGRP any proline in a peptide can be found in the in vivo data.…”

“…The identification of these substrates led to new hypotheses about Prep function, which were tested in vivo using pharmacological Prep inhibitors. Interestingly, several of these experiments suggested that Prep inhibition would lead to improved cognitive function in mammals, which was later verified (15)(16)(17)(18). However, the underlying mechanism for this improvement is still under investigation because some of the Prep substrates predicted to be responsible for this effect were unaffected, or only modestly affected, upon Prep inhibition (19)(20)(21).…”